pathway_id pathway_name entitya regulator_location typea ida databasea entityb target_location typeb idb databaseb effect mechanism residue sequence tax_id cell_data tissue_data modulator_complex target_complex modificationa modaseq modificationb modbseq pmid direct notes annotator sentence signor_id score SIGNOR-AAAM Aspartate and asparagine metabolism ASPA protein P45381 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267528 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267503 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ATF4 factor protein P18848 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11960987 f miannu Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation. SIGNOR-253747 0.638 SIGNOR-AAAM Aspartate and asparagine metabolism CSAD protein Q9Y600 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267549 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268071 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ADSS1 protein Q8N142 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267346 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267515 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267519 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 f miannu A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. SIGNOR-267821 0.7 SIGNOR-AAAM Aspartate and asparagine metabolism acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267520 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GADL1 protein Q6ZQY3 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267546 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GAD2 protein Q05329 UNIPROT gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267555 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ASPG protein Q86U10 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267538 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267544 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267547 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ASPA protein P45381 UNIPROT acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity chemical modification 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267527 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism NAALAD2 protein Q9Y3Q0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267543 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267553 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 11863375 t miannu Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266924 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267505 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ADSS2 protein P30520 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267834 0.7 SIGNOR-AAAM Aspartate and asparagine metabolism ASNS protein P08243 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267534 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267513 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267529 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism NAALAD2 protein Q9Y3Q0 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267542 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267536 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ADSS2 protein P30520 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267345 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267550 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267517 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-268085 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267512 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ASPG protein Q86U10 UNIPROT ammonia smallmolecule CHEBI:16134 ChEBI up-regulates quantity chemical modification 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267539 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267530 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267511 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ASNS protein P08243 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267535 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ASNS protein P08243 UNIPROT L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267533 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267504 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267514 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267525 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GAD1 protein Q99259 UNIPROT gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267552 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism ADSS1 protein Q8N142 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267835 0.7 SIGNOR-AAAM Aspartate and asparagine metabolism L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267516 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism NAT8L protein Q8N9F0 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267524 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT2 protein P00505 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267518 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267540 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 19524112 t miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. SIGNOR-267523 0.8 SIGNOR-AAAM Aspartate and asparagine metabolism GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267506 0.8 SIGNOR-AC Adipogenesis NR3C1 factor protein P04150 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-235346 0.47 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-252611 0.73 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236159 0.866 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 17601773 t fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-156509 0.41 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.911 SIGNOR-AC Adipogenesis SMAD3 protein P84022 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-241924 0.385 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-236163 0.866 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates activity phosphorylation Thr230 GHPTPPPtPVPSPHP 10090 BTO:0000944 10567568 t Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. SIGNOR-251232 0.388 SIGNOR-AC Adipogenesis GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232134 0.732 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity, SIGNOR-217734 0.732 SIGNOR-AC Adipogenesis CEBPB factor protein P17676 UNIPROT KLF5 factor protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210004 0.69 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT FOXO1 factor protein Q12778 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-209647 0.866 SIGNOR-AC Adipogenesis RPS6KA5 protein O75582 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.721 SIGNOR-AC Adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. SIGNOR-250749 0.732 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 t We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188 SIGNOR-251644 0.472 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-147963 0.683 SIGNOR-AC Adipogenesis CEBPD factor protein P49716 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 f gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. SIGNOR-253062 0.578 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.911 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-123606 0.648 SIGNOR-AC Adipogenesis NR3C1 factor protein P04150 UNIPROT CEBPD factor protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 t The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 0.324 SIGNOR-AC Adipogenesis SMAD3 protein P84022 UNIPROT CEBPB factor protein P17676 UNIPROT down-regulates activity binding 10090 12524424 t gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters SIGNOR-250567 0.576 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT KLF5 factor protein Q13887 UNIPROT down-regulates phosphorylation Ser303 QATYFPPsPPSSEPG 9606 24398687 t lperfetto Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5 SIGNOR-203627 0.376 SIGNOR-AC Adipogenesis NR3C1 factor protein P04150 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 t lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 0.476 SIGNOR-AC Adipogenesis GATA2 factor protein P23769 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates activity 9606 20510530 t fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 0.382 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.911 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT GATA2 factor protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-135614 0.544 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000142 10226025 t acerquone Protein kinase b (pkb) is activated by phosphorylation of thr308 and of ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (pdk1) but the identity of the kinase that phosphorylates ser473 (provisionally termed pdk2) is unknown. SIGNOR-67363 0.73 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT NR3C1 factor protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249427 0.299 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.911 SIGNOR-AC Adipogenesis IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000944 11416002 t lperfetto To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1 SIGNOR-235487 0.71 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 t gcesareni Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. SIGNOR-175675 0.73 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-AC Adipogenesis PPARG factor protein P37231 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f Dislodging hdac1 from the promoter lperfetto These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-235358 0.642 SIGNOR-AC Adipogenesis INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.932 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 t gcesareni Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. SIGNOR-252531 0.683 SIGNOR-AC Adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AC Adipogenesis CEBPA factor protein P49715 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 f gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role. SIGNOR-250562 0.7 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.911 SIGNOR-AC Adipogenesis KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 10882715 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-78911 0.84 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126732 0.732 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 t acerquone We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies. SIGNOR-67367 0.73 SIGNOR-AC Adipogenesis KRAS protein P01116 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k. SIGNOR-175207 0.697 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.911 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126740 0.732 SIGNOR-AC Adipogenesis INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.911 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-236206 0.866 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249573 0.2 SIGNOR-AC Adipogenesis PIK3CB protein P42338 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 21779497 t lperfetto The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175241 0.8 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. SIGNOR-232236 0.2 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates activity phosphorylation Thr226 HLQPGHPtPPPTPVP 10090 BTO:0000944 10567568 t Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. SIGNOR-251231 0.388 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPB factor protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000551 19723873 t gcesareni Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction. SIGNOR-238303 0.2 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT NR3C1 factor protein P04150 UNIPROT up-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249426 0.299 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-252588 0.683 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249572 0.2 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 t fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-196372 0.41 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates quantity by expression phosphorylation 10090 BTO:0000011 12270934 t lperfetto Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression. SIGNOR-235334 0.2 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates phosphorylation Thr226 GSSGSLStSSSSSPP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 t fspada However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. SIGNOR-210129 0.472 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 phosphorylation:Ser473 RPHFPQFsYSASGTA 12167717 t gcesareni Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation. SIGNOR-91354 0.73 SIGNOR-AC Adipogenesis TGFBR1 receptor protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 f MARCO ROSINA TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad SIGNOR-255033 0.32 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182975 0.732 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-252612 0.73 SIGNOR-AC Adipogenesis PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249629 0.73 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase. SIGNOR-250750 0.732 SIGNOR-AC Adipogenesis NR3C1 factor protein P04150 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250561 0.403 SIGNOR-AC Adipogenesis NR3C1 factor protein P04150 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates activity binding 10116 9428795 t We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 0.476 SIGNOR-AC Adipogenesis PPARG factor protein P37231 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 0.7 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126736 0.732 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.911 SIGNOR-AC Adipogenesis KLF5 factor protein Q13887 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210010 0.605 SIGNOR-AC Adipogenesis INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.911 SIGNOR-AC Adipogenesis IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000887 14623899 t lperfetto As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation SIGNOR-236618 0.71 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249574 0.2 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182971 0.732 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t lperfetto In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-244614 0.2 SIGNOR-AC Adipogenesis CREB1 factor protein P16220 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 f lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 0.584 SIGNOR-AC Adipogenesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-AC Adipogenesis GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-AC Adipogenesis TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.838 SIGNOR-AC Adipogenesis IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 t lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. SIGNOR-236614 0.796 SIGNOR-AC Adipogenesis FOXO1 factor protein Q12778 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 f lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 0.566 SIGNOR-AC Adipogenesis CEBPB factor protein P17676 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 t fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome SIGNOR-143952 0.719 SIGNOR-AC Adipogenesis GSK3B protein P49841 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant SIGNOR-251233 0.682 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-252549 0.762 SIGNOR-AC Adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182967 0.732 SIGNOR-AC Adipogenesis KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.84 SIGNOR-AC Adipogenesis CDK2 protein P24941 UNIPROT FOXO1 factor protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. SIGNOR-150028 0.638 SIGNOR-AC Adipogenesis AKT1 protein P31749 UNIPROT NR3C1 factor protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 t lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus SIGNOR-252543 0.503 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251598 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT BAX protein Q07812 UNIPROT up-regulates phosphorylation Ser163 GGWDGLLsYFGTPTW 9606 BTO:0000938 15525785 t lperfetto Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163 SIGNOR-130141 0.384 SIGNOR-AD Alzheimer TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-AD Alzheimer TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-AD Alzheimer GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60651 0.442 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. SIGNOR-164655 0.729 SIGNOR-AD Alzheimer PSEN1 receptor protein P49768 UNIPROT gamma-secretase receptor complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-217746 0.956 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171046 0.729 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251596 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT PSEN1 receptor protein P49768 UNIPROT down-regulates activity phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-153627 0.61 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249343 0.729 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages SIGNOR-256025 0.923 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251590 0.695 SIGNOR-AD Alzheimer CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.787 SIGNOR-AD Alzheimer CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251585 0.2 SIGNOR-AD Alzheimer CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251582 0.912 SIGNOR-AD Alzheimer BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 12242151 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-92945 0.817 SIGNOR-AD Alzheimer MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotypesList phenotype SIGNOR-PH58 SIGNOR down-regulates 9606 11578751 f lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly SIGNOR-251639 0.7 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249355 0.729 SIGNOR-AD Alzheimer TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain SIGNOR-245029 0.799 SIGNOR-AD Alzheimer Amyloid_fibril_formation phenotypesList phenotype SIGNOR-PH59 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death SIGNOR-251640 0.7 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT PSEN1 receptor protein P49768 UNIPROT down-regulates activity phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 SIGNOR-C110 17360711 t gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. SIGNOR-153631 0.61 SIGNOR-AD Alzheimer BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 f gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes SIGNOR-160039 0.687 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 14732063 t miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253593 0.923 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249350 0.729 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249347 0.729 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249345 0.729 SIGNOR-AD Alzheimer CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261743 0.417 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171042 0.729 SIGNOR-AD Alzheimer CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261749 0.417 SIGNOR-AD Alzheimer TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 14585074 t amattioni Tradd recruits caspase-8 SIGNOR-118591 0.906 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251600 0.695 SIGNOR-AD Alzheimer BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 t amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. SIGNOR-73902 0.817 SIGNOR-AD Alzheimer CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.787 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 t amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. SIGNOR-171767 0.707 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser400 AKTSTRSsAKTLKNR 9606 BTO:0000590 20679343 t lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167290 0.729 SIGNOR-AD Alzheimer BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-AD Alzheimer PSEN1 receptor protein P49768 UNIPROT gamma-secretase receptor complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209705 0.956 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249352 0.729 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261760 0.377 SIGNOR-AD Alzheimer FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-AD Alzheimer gamma-secretase receptor complex SIGNOR-C98 SIGNOR APP receptor protein P05067 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 19958215 t lperfetto The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP). SIGNOR-251576 0.603 SIGNOR-AD Alzheimer CDK5R1 protein Q15078 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 t lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity SIGNOR-250682 0.941 SIGNOR-AD Alzheimer BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.615 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251593 0.695 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 t lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-251587 0.695 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251597 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249351 0.729 SIGNOR-AD Alzheimer NCSTN receptor protein Q92542 UNIPROT gamma-secretase receptor complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 t lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) SIGNOR-209711 0.964 SIGNOR-AD Alzheimer GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 t lperfetto Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. SIGNOR-249342 0.442 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 17078951 t The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 SIGNOR-150360 0.729 SIGNOR-AD Alzheimer APP receptor protein P05067 UNIPROT Amyloid_fibril_formation phenotypesList phenotype SIGNOR-PH59 SIGNOR up-regulates 9606 11578751 f lperfetto Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). SIGNOR-251638 0.7 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 t amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. SIGNOR-81808 0.707 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249354 0.729 SIGNOR-AD Alzheimer PSEN1 receptor protein P49768 UNIPROT gamma-secretase receptor complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-217743 0.956 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT APP receptor protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS -1 8764598 t The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). SIGNOR-251220 0.564 SIGNOR-AD Alzheimer CASP3 protein P42574 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-89244 0.7 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249346 0.729 SIGNOR-AD Alzheimer NCSTN receptor protein Q92542 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates binding 9606 12603837 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-98724 0.964 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 21443865 t The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B). SIGNOR-255486 0.729 SIGNOR-AD Alzheimer NCSTN receptor protein Q92542 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-118852 0.964 SIGNOR-AD Alzheimer BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 17289999 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-152929 0.817 SIGNOR-AD Alzheimer APAF1 protein O14727 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 t lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  SIGNOR-256431 0.87 SIGNOR-AD Alzheimer NAE1 protein Q13564 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway SIGNOR-251579 0.7 SIGNOR-AD Alzheimer BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-131442 0.817 SIGNOR-AD Alzheimer BID protein P55957 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 9727492 f Translocation from Mitochondria to Cytosol lperfetto TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c. SIGNOR-59224 0.574 SIGNOR-AD Alzheimer NCSTN receptor protein Q92542 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates binding 9606 12471034 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-96253 0.964 SIGNOR-AD Alzheimer CAPN1 protein P07384 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251586 0.303 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 20679343 t The effect has been demonstrated using P10636-8 lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167294 0.729 SIGNOR-AD Alzheimer MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotypesList phenotype SIGNOR-PH58 SIGNOR up-regulates 9606 11578751 f lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly SIGNOR-251642 0.7 SIGNOR-AD Alzheimer TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-251601 0.695 SIGNOR-AD Alzheimer BCL2 protein P10415 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity 9606 BTO:0000567 12624108 f lperfetto Bcl-2 blocked the release of mitochondrial cytochrome c SIGNOR-99063 0.628 SIGNOR-AD Alzheimer NCSTN receptor protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 t Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. SIGNOR-81936 0.939 SIGNOR-AD Alzheimer APP receptor protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 f gcesareni These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons. SIGNOR-144057 0.42 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261744 0.338 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249344 0.729 SIGNOR-AD Alzheimer CASP3 protein P42574 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261756 0.47 SIGNOR-AD Alzheimer Neurofibrillary tangle formation phenotypesList phenotype SIGNOR-PH58 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11578751 f lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death SIGNOR-251641 0.7 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 BTO:0000661 10364179 f Translocation from Mitochondria to Cytosol lperfetto Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect. SIGNOR-68225 0.503 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251594 0.695 SIGNOR-AD Alzheimer CAPN1 protein P07384 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251583 0.548 SIGNOR-AD Alzheimer GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 7566348 t fstefani The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau. SIGNOR-29364 0.442 SIGNOR-AD Alzheimer TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-AD Alzheimer BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-AD Alzheimer CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.787 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251588 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249349 0.729 SIGNOR-AD Alzheimer CAPN1 protein P07384 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains SIGNOR-251584 0.344 SIGNOR-AD Alzheimer BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251592 0.695 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251591 0.695 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251589 0.695 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-AD Alzheimer APP receptor protein P05067 UNIPROT NAE1 protein Q13564 UNIPROT up-regulates activity binding 9606 BTO:0000590 25568892 t lperfetto Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. SIGNOR-251577 0.724 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261752 0.338 SIGNOR-AD Alzheimer Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-256471 0.729 SIGNOR-AD Alzheimer BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249348 0.729 SIGNOR-AD Alzheimer TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 17151142 t miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 0.923 SIGNOR-AD Alzheimer CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.787 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60655 0.729 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251595 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 t lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? SIGNOR-167286 0.729 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-90612 0.7 SIGNOR-AD Alzheimer CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251599 0.695 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249353 0.729 SIGNOR-AD Alzheimer CAPN1 protein P07384 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251581 0.556 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. SIGNOR-164651 0.729 SIGNOR-AD Alzheimer GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr534 SRTPSLPtPPTREPK 9606 17078951 t The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 SIGNOR-150364 0.729 SIGNOR-AD Alzheimer CASP8 protein Q14790 UNIPROT PSEN1 receptor protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261754 0.377 SIGNOR-AG Axon guidance Actin_cytoskeleton_reorganization phenotypesList phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268384 0.7 SIGNOR-AG Axon guidance PKA proteinfamily SIGNOR-PF17 SIGNOR EVL protein Q9UI08 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268287 0.2 SIGNOR-AG Axon guidance NTN1 extracellular protein O95631 UNIPROT DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 t miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. SIGNOR-268376 0.724 SIGNOR-AG Axon guidance calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 9651347 t gcesareni Our results indicate that ca2+ ions not only anchor the protein to membrane surfaces but also induce conformational changes resulting in pkc activation. SIGNOR-58506 0.8 SIGNOR-AG Axon guidance SLIT2 extracellular protein O94813 UNIPROT ROBO3 receptor protein Q96MS0 UNIPROT up-regulates activity binding -1 16226035 t miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268381 0.651 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT Chemoattraction_of_axon phenotypesList phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 BTO:0001484 25881791 f miannu DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction SIGNOR-268163 0.7 SIGNOR-AG Axon guidance UNC5A protein Q6ZN44 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268164 0.647 SIGNOR-AG Axon guidance CFL1 protein P23528 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR down-regulates 9606 16226035 f miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268382 0.7 SIGNOR-AG Axon guidance NTN1 extracellular protein O95631 UNIPROT DCC protein P43146 UNIPROT up-regulates activity binding 9606 BTO:0001484 25881791 t miannu DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. SIGNOR-268162 0.906 SIGNOR-AG Axon guidance calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 t It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255491 0.8 SIGNOR-AG Axon guidance SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 t gcesareni Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation. SIGNOR-118206 0.685 SIGNOR-AG Axon guidance ACTN1 protein P12814 UNIPROT F-actin_assembly phenotypesList phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 27871158 t lperfetto Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios SIGNOR-261852 0.7 SIGNOR-AG Axon guidance UNC5 proteinfamily SIGNOR-PF98 SIGNOR DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268168 0.2 SIGNOR-AG Axon guidance PRKG1 protein Q13976 UNIPROT ENAH protein Q8N8S7 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts. PKG may preferentially phosphorylate sites of Ena/VASP proteins that reduce or inactivate these proteins. Inactivated Ena/VASP proteins dissociate from actin filaments, allowing capping proteins to bind and block monomer addition to plus ends, resulting in filament retraction. SIGNOR-268288 0.31 SIGNOR-AG Axon guidance NTN1 extracellular protein O95631 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268183 0.849 SIGNOR-AG Axon guidance F-actin_assembly phenotypesList phenotype SIGNOR-PH18 SIGNOR Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268387 0.7 SIGNOR-AG Axon guidance ENAH protein Q8N8S7 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268389 0.7 SIGNOR-AG Axon guidance CAMK2A protein Q9UQM7 UNIPROT Chemoattraction_of_axon phenotypesList phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 15363394 f miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. SIGNOR-268385 0.7 SIGNOR-AG Axon guidance Actin_cytoskeleton_reorganization phenotypesList phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. SIGNOR-268383 0.7 SIGNOR-AG Axon guidance PRKG1 protein Q13976 UNIPROT EVL protein Q9UI08 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268290 0.2 SIGNOR-AG Axon guidance PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser352 TSGFQPVsIKPSKAD 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268180 0.2 SIGNOR-AG Axon guidance Netrin proteinfamily SIGNOR-PF97 SIGNOR NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 21558366 t miannu In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM). SIGNOR-268172 0.2 SIGNOR-AG Axon guidance UNC5A protein Q6ZN44 UNIPROT PICK1 protein Q9NRD5 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1 SIGNOR-268181 0.295 SIGNOR-AG Axon guidance PICK1 protein Q9NRD5 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268178 0.796 SIGNOR-AG Axon guidance DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268401 0.7 SIGNOR-AG Axon guidance PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268289 0.73 SIGNOR-AG Axon guidance EVL protein Q9UI08 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268391 0.7 SIGNOR-AG Axon guidance PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser532 EPSPDSWsLRLKKQS 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268179 0.2 SIGNOR-AG Axon guidance SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway SIGNOR-188352 0.575 SIGNOR-AG Axon guidance Netrin proteinfamily SIGNOR-PF97 SIGNOR UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268174 0.849 SIGNOR-AG Axon guidance CACNA1A receptor protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264323 0.8 SIGNOR-AG Axon guidance CDC42 protein P60953 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 t miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. SIGNOR-268424 0.855 SIGNOR-AG Axon guidance RAPH1 protein Q70E73 UNIPROT EVL protein Q9UI08 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268427 0.356 SIGNOR-AG Axon guidance FSCN1 protein Q16658 UNIPROT Actin_cytoskeleton_reorganization phenotypesList phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 BTO:0000526 21706053 f miannu Plexin-B3 interacts with the actin-binding protein fascin-1. The present finding suggests fascin-1 as a potential effector of plexin-B3 to mediate the signal of Sema5A in glioma cells.Sema5A and plexin-B3 remodel F-actin cytoskeleton and induce fascin-1 translocation in glioma cells. SIGNOR-268375 0.7 SIGNOR-AG Axon guidance RGMA protein Q96B86 UNIPROT NEO1 protein Q92859 UNIPROT down-regulates activity binding 10090 18485097 t miannu Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.  SIGNOR-268388 0.781 SIGNOR-AG Axon guidance Calcineurin complex SIGNOR-C155 SIGNOR Chemorepulsion_of_axon phenotypesList phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 15363394 f miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. SIGNOR-268386 0.7 SIGNOR-AG Axon guidance DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268396 0.7 SIGNOR-AG Axon guidance RAPH1 protein Q70E73 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268425 0.564 SIGNOR-AG Axon guidance NTN1 extracellular protein O95631 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity post transcriptional regulation 443947 BTO:0001036 16980963 t miannu Netrin-1 induces β-actin translation driven by its 3’UTR. SIGNOR-268161 0.287 SIGNOR-AG Axon guidance ROBO2 receptor protein Q9HCK4 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268378 0.262 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 29479476 t miannu The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. Axon guidance assays confirm that this DCC/FAK complex is physiologically essential for netrin-1-induced chemoattraction. SIGNOR-268370 0.704 SIGNOR-AG Axon guidance BAIAP2 protein Q9UQB8 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 t miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. SIGNOR-268423 0.547 SIGNOR-AG Axon guidance PKA proteinfamily SIGNOR-PF17 SIGNOR ENAH protein Q8N8S7 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268285 0.2 SIGNOR-AG Axon guidance MYO10 protein Q9HD67 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity relocalization 10090 BTO:0000938 17237772 t miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. SIGNOR-268282 0.666 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 15494734 t miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. SIGNOR-268371 0.704 SIGNOR-AG Axon guidance ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity guanine nucleotide exchange factor 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma. SIGNOR-268436 0.802 SIGNOR-AG Axon guidance SEMA5A protein Q13591 UNIPROT PLXNB3 protein Q9ULL4 UNIPROT up-regulates activity binding 10090 BTO:0000944 15218527 t miannu Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). SIGNOR-268373 0.604 SIGNOR-AG Axon guidance PLXNB3 protein Q9ULL4 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity binding 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays. SIGNOR-268435 0.254 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 15494734 t miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. SIGNOR-268372 0.512 SIGNOR-AG Axon guidance NEO1 protein Q92859 UNIPROT Chemoattraction_of_axon phenotypesList phenotype SIGNOR-PH197 SIGNOR up-regulates 17204444 f miannu Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. SIGNOR-268395 0.7 SIGNOR-AG Axon guidance calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 t miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-255462 0.8 SIGNOR-AG Axon guidance Netrin proteinfamily SIGNOR-PF97 SIGNOR DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 t miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. SIGNOR-268173 0.2 SIGNOR-AG Axon guidance PLXNB3 protein Q9ULL4 UNIPROT FSCN1 protein Q16658 UNIPROT up-regulates activity 10090 BTO:0000526 21706053 f miannu Sema5A regulates the phosphorylation states of fascin-1 through plexin-B3. SIGNOR-268374 0.341 SIGNOR-AG Axon guidance ROBO3 receptor protein Q96MS0 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268379 0.2 SIGNOR-AG Axon guidance UNC5 proteinfamily SIGNOR-PF98 SIGNOR Chemorepulsion_of_axon phenotypesList phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion SIGNOR-268177 0.7 SIGNOR-AG Axon guidance PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity phosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0004055 11369769 t lperfetto The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments. SIGNOR-108329 0.551 SIGNOR-AG Axon guidance UNC5A protein Q6ZN44 UNIPROT Chemorepulsion_of_axon phenotypesList phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion SIGNOR-268182 0.7 SIGNOR-AG Axon guidance ACTB protein P60709 UNIPROT F-actin_assembly phenotypesList phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 t lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments SIGNOR-261879 0.7 SIGNOR-AG Axon guidance PKA proteinfamily SIGNOR-PF17 SIGNOR VASP protein P50552 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268286 0.2 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT CACNA1A receptor protein O00555 UNIPROT up-regulates activity 9606 12827203 t miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. SIGNOR-268293 0.2 SIGNOR-AG Axon guidance MYO10 protein Q9HD67 UNIPROT Actin_cytoskeleton_reorganization phenotypesList phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 27580874 f miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. SIGNOR-268283 0.7 SIGNOR-AG Axon guidance RAPH1 protein Q70E73 UNIPROT VASP protein P50552 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268426 0.602 SIGNOR-AG Axon guidance NTN1 extracellular protein O95631 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 t miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. SIGNOR-268169 0.819 SIGNOR-AG Axon guidance VASP protein P50552 UNIPROT Axonal_growth_cone_formation phenotypesList phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268390 0.7 SIGNOR-AG Axon guidance RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 10090 BTO:0000944 19171758 t miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. SIGNOR-265554 0.723 SIGNOR-AG Axon guidance SLIT2 extracellular protein O94813 UNIPROT ROBO2 receptor protein Q9HCK4 UNIPROT up-regulates activity binding -1 16226035 t miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268380 0.857 SIGNOR-AG Axon guidance DCC protein P43146 UNIPROT MYO10 protein Q9HD67 UNIPROT up-regulates activity binding 10090 BTO:0000938 17237772 t miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. SIGNOR-268281 0.666 SIGNOR-AML Acute Myeloid Leukemia GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-AML Acute Myeloid Leukemia MLL-ENL fusion protein SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255870 0.2 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22897849 f miannu ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR SIGNOR-256127 0.448 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 t Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 0.2 SIGNOR-AML Acute Myeloid Leukemia CDK6 protein Q00534 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169334 0.593 SIGNOR-AML Acute Myeloid Leukemia DNMT3A protein Q9Y6K1 UNIPROT MEIS1 factor protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 f miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. SIGNOR-256125 0.338 SIGNOR-AML Acute Myeloid Leukemia CBLB protein Q13191 UNIPROT KIT receptor protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260105 0.332 SIGNOR-AML Acute Myeloid Leukemia NCOA1 factor protein Q15788 UNIPROT RARA factor protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255932 0.691 SIGNOR-AML Acute Myeloid Leukemia PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255754 0.661 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 factor protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-244236 0.2 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells SIGNOR-256583 0.7 SIGNOR-AML Acute Myeloid Leukemia PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248349 0.487 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11090075 f Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins. SIGNOR-255725 0.2 SIGNOR-AML Acute Myeloid Leukemia PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255982 0.646 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SIGNOR-AML Acute Myeloid Leukemia MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255867 0.2 SIGNOR-AML Acute Myeloid Leukemia RAD21 protein O60216 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 t miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells SIGNOR-259973 0.29 SIGNOR-AML Acute Myeloid Leukemia SOX4 factor protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000038 17875931 t irozzo We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein. SIGNOR-256138 0.576 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JUN factor protein P05412 UNIPROT down-regulates activity binding 9606 BTO:0004136 12393465 t RUNX1-RUNX1T1 fusion protein (AML-ETO) apalma Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun. SIGNOR-255670 0.2 SIGNOR-AML Acute Myeloid Leukemia BAD protein Q92934 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256259 0.7 SIGNOR-AML Acute Myeloid Leukemia NOTCH1 protein P46531 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 f flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages SIGNOR-241998 0.7 SIGNOR-AML Acute Myeloid Leukemia BCL2L1 protein Q07817 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 f fcortellessa Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition SIGNOR-261683 0.7 SIGNOR-AML Acute Myeloid Leukemia CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates activity 9606 11090075 t apalma We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway. SIGNOR-256373 0.2 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTPRC receptor protein P08575 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-255686 0.2 SIGNOR-AML Acute Myeloid Leukemia PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 SIGNOR-AML Acute Myeloid Leukemia NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-AML Acute Myeloid Leukemia ZBTB16 factor protein Q05516 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF overexpression leads to apoptosis. SIGNOR-261686 0.7 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates activity binding 9606 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255931 0.29 SIGNOR-AML Acute Myeloid Leukemia CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44557 0.865 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 t irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. SIGNOR-255820 0.2 SIGNOR-AML Acute Myeloid Leukemia IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 SIGNOR-AML Acute Myeloid Leukemia MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255876 0.2 SIGNOR-AML Acute Myeloid Leukemia MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260127 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PARP1 factor protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  SIGNOR-261554 0.254 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML Acute Myeloid Leukemia miR-155 mirna URS000062749E_9606 RNAcentral FOS factor protein P01100 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 24708856 t miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. SIGNOR-255766 0.4 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 15769897 t we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y SIGNOR-261540 0.432 SIGNOR-AML Acute Myeloid Leukemia DOT1L protein Q8TEK3 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255880 0.2 SIGNOR-AML Acute Myeloid Leukemia SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-AML Acute Myeloid Leukemia DOT1L protein Q8TEK3 UNIPROT HOXA9 factor protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256141 0.466 SIGNOR-AML Acute Myeloid Leukemia MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-AML Acute Myeloid Leukemia MEN1 protein O00255 UNIPROT MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255868 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity SIGNOR-255584 0.565 SIGNOR-AML Acute Myeloid Leukemia BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.641 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251148 0.432 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15574429 f Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity SIGNOR-261532 0.374 SIGNOR-AML Acute Myeloid Leukemia GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0001516 23246379 t Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation SIGNOR-255946 0.341 SIGNOR-AML Acute Myeloid Leukemia DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-255809 0.393 SIGNOR-AML Acute Myeloid Leukemia PTPRJ receptor protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 t gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. SIGNOR-252727 0.265 SIGNOR-AML Acute Myeloid Leukemia MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 SIGNOR-AML Acute Myeloid Leukemia PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248348 0.487 SIGNOR-AML Acute Myeloid Leukemia PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SIGNOR-AML Acute Myeloid Leukemia SPI1 factor protein P17947 UNIPROT miR-338 mirna URS000075E706_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255886 0.4 SIGNOR-AML Acute Myeloid Leukemia CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 SIGNOR-AML Acute Myeloid Leukemia MECOM factor protein Q03112 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 t irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. SIGNOR-255716 0.507 SIGNOR-AML Acute Myeloid Leukemia MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML Acute Myeloid Leukemia AEP complex complex SIGNOR-C117 SIGNOR HOXA9 factor protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-255879 0.423 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.909 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 t gcesareni BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation SIGNOR-248199 0.2 SIGNOR-AML Acute Myeloid Leukemia MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w SIGNOR-151787 0.718 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246289 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.909 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-AML Acute Myeloid Leukemia MYC factor protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 f USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261560 0.513 SIGNOR-AML Acute Myeloid Leukemia GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. SIGNOR-114704 0.9 SIGNOR-AML Acute Myeloid Leukemia KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation. SIGNOR-170594 0.484 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-236502 0.2 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-AML Acute Myeloid Leukemia BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0002181 17379597 t irozzo BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. SIGNOR-259193 0.452 SIGNOR-AML Acute Myeloid Leukemia RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.643 SIGNOR-AML Acute Myeloid Leukemia CEBPA factor protein P49715 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001056 11283671 t apalma Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells. SIGNOR-255673 0.2 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR NFY complex SIGNOR-C1 SIGNOR up-regulates activity binding 9606 BTO:0000972 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255747 0.2 SIGNOR-AML Acute Myeloid Leukemia MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162314 0.627 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255577 0.7 SIGNOR-AML Acute Myeloid Leukemia MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-AML Acute Myeloid Leukemia MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM factor protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-260107 0.2 SIGNOR-AML Acute Myeloid Leukemia AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001412 31900833 t miannu Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. SIGNOR-260097 0.2 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization binding 10090 12370803 t irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255810 0.47 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.909 SIGNOR-AML Acute Myeloid Leukemia HOXA9 factor protein P31269 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255864 0.7 SIGNOR-AML Acute Myeloid Leukemia DOT1L protein Q8TEK3 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256143 0.417 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-AML Acute Myeloid Leukemia SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t gcesareni The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-66949 0.681 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.813 SIGNOR-AML Acute Myeloid Leukemia AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256135 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT ZBTB16 factor protein Q05516 UNIPROT down-regulates activity 10090 BTO:0002181 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261537 0.322 SIGNOR-AML Acute Myeloid Leukemia WT1 factor protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23042785 t irozzo Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. SIGNOR-255904 0.394 SIGNOR-AML Acute Myeloid Leukemia prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 f apalma Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255685 0.8 SIGNOR-AML Acute Myeloid Leukemia BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000141 18179858 t irozzo KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models. SIGNOR-256121 0.708 SIGNOR-AML Acute Myeloid Leukemia CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 f apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255586 0.2 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.785 SIGNOR-AML Acute Myeloid Leukemia DNMT3A protein Q9Y6K1 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255808 0.483 SIGNOR-AML Acute Myeloid Leukemia DOT1L protein Q8TEK3 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0001939 26199140 t 1 miannu Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1 SIGNOR-239362 0.345 SIGNOR-AML Acute Myeloid Leukemia CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 t gcesareni Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139649 0.495 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255885 0.4 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 BTO:0004136 10208431 t miannu The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex SIGNOR-260094 0.2 SIGNOR-AML Acute Myeloid Leukemia MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000830 15526160 t miannu Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase SIGNOR-254949 0.708 SIGNOR-AML Acute Myeloid Leukemia PHF6 protein Q8IWS0 UNIPROT UBTF factor protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf SIGNOR-200133 0.285 SIGNOR-AML Acute Myeloid Leukemia miR-199a mirna URS0000759977_9606 RNAcentral MTOR protein P42345 UNIPROT up-regulates activity 9606 26055960 t miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. SIGNOR-255803 0.4 SIGNOR-AML Acute Myeloid Leukemia MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-AML Acute Myeloid Leukemia NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-252700 0.662 SIGNOR-AML Acute Myeloid Leukemia PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 f miannu The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-255732 0.7 SIGNOR-AML Acute Myeloid Leukemia INPP5D protein Q92835 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 12421919 t gcesareni Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten SIGNOR-252428 0.8 SIGNOR-AML Acute Myeloid Leukemia MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-149774 0.603 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 t miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. SIGNOR-260124 0.425 SIGNOR-AML Acute Myeloid Leukemia PTGS2 protein P35354 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification 9606 16540375 t Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES) SIGNOR-255684 0.8 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity SIGNOR-236506 0.2 SIGNOR-AML Acute Myeloid Leukemia FZD4 receptor protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258955 0.594 SIGNOR-AML Acute Myeloid Leukemia FOXO factor proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-252928 0.2 SIGNOR-AML Acute Myeloid Leukemia MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML Acute Myeloid Leukemia TET2 protein Q6N021 UNIPROT WT1 factor protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.467 SIGNOR-AML Acute Myeloid Leukemia PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9534 8943354 t Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 SIGNOR-248466 0.718 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-260120 0.2 SIGNOR-AML Acute Myeloid Leukemia SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242628 0.708 SIGNOR-AML Acute Myeloid Leukemia AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.909 SIGNOR-AML Acute Myeloid Leukemia BCOR protein Q6W2J9 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256011 0.7 SIGNOR-AML Acute Myeloid Leukemia MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-AML Acute Myeloid Leukemia USP22 protein Q9UPT9 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 26049753 t USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261561 0.555 SIGNOR-AML Acute Myeloid Leukemia SH2B3 protein Q9UQQ2 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 10090 BTO:0002882 18618018 t miannu we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions. SIGNOR-260075 0.631 SIGNOR-AML Acute Myeloid Leukemia GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-AML Acute Myeloid Leukemia NCOA1 factor protein Q15788 UNIPROT ASXL1 protein Q8IXJ9 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255924 0.29 SIGNOR-AML Acute Myeloid Leukemia MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255877 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT NCOR2 factor protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261538 0.262 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.909 SIGNOR-AML Acute Myeloid Leukemia MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. SIGNOR-260130 0.2 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246285 0.2 SIGNOR-AML Acute Myeloid Leukemia HHEX protein Q03014 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 BTO:0000089 26728554 f Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal. SIGNOR-256306 0.7 SIGNOR-AML Acute Myeloid Leukemia MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162318 0.627 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247146 0.2 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 0.2 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004850 23645839 f miannu AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. SIGNOR-255683 0.2 SIGNOR-AML Acute Myeloid Leukemia FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243545 0.754 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-AML Acute Myeloid Leukemia PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax SIGNOR-259418 0.2 SIGNOR-AML Acute Myeloid Leukemia CCND1 factor protein P24385 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. SIGNOR-260014 0.7 SIGNOR-AML Acute Myeloid Leukemia CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-AML Acute Myeloid Leukemia FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-AML Acute Myeloid Leukemia KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 f Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. SIGNOR-261518 0.333 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity transcriptional regulation 9606 26059451 t … these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells SIGNOR-255631 0.334 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12370803 f irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255811 0.47 SIGNOR-AML Acute Myeloid Leukemia KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-AML Acute Myeloid Leukemia STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-AML Acute Myeloid Leukemia DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255881 0.2 SIGNOR-AML Acute Myeloid Leukemia CBL protein P22681 UNIPROT KIT receptor protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260104 0.597 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252824 0.909 SIGNOR-AML Acute Myeloid Leukemia GSK3B protein P49841 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. SIGNOR-144818 0.775 SIGNOR-AML Acute Myeloid Leukemia SOX4 factor protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0003104 24970928 t irozzo The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes. SIGNOR-256139 0.576 SIGNOR-AML Acute Myeloid Leukemia ZBTB16 factor protein Q05516 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest. SIGNOR-261685 0.7 SIGNOR-AML Acute Myeloid Leukemia MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 extracellular protein P05019 UNIPROT down-regulates quantity post transcriptional regulation 9606 25477897 t miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1 SIGNOR-255793 0.4 SIGNOR-AML Acute Myeloid Leukemia MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162322 0.627 SIGNOR-AML Acute Myeloid Leukemia RELA factor protein Q04206 UNIPROT NCOR2 factor protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 t Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export. SIGNOR-261539 0.415 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246281 0.2 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19797526 f We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding. SIGNOR-255726 0.2 SIGNOR-AML Acute Myeloid Leukemia MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-AML Acute Myeloid Leukemia NUP98 Fusion fusion protein SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32344427 f miannu NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition. SIGNOR-261505 0.2 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 BTO:0000093 8415704 f miannu PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site SIGNOR-261507 0.2 SIGNOR-AML Acute Myeloid Leukemia SOX4 factor protein Q06945 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors. SIGNOR-255676 0.7 SIGNOR-AML Acute Myeloid Leukemia DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 t amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. SIGNOR-134285 0.799 SIGNOR-AML Acute Myeloid Leukemia MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260126 0.2 SIGNOR-AML Acute Myeloid Leukemia HOXA9 factor protein P31269 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.647 SIGNOR-AML Acute Myeloid Leukemia MEIS1 factor protein O00470 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 SIGNOR-AML Acute Myeloid Leukemia CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates activity binding 10090 BTO:0002882 26387755 t Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53. SIGNOR-255737 0.2 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 22806893 t irozzo SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation. SIGNOR-256140 0.669 SIGNOR-AML Acute Myeloid Leukemia GSK3B protein P49841 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc SIGNOR-118844 0.709 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT FZD4 receptor protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002882 15650056 f AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3. SIGNOR-261533 0.2 SIGNOR-AML Acute Myeloid Leukemia MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260128 0.2 SIGNOR-AML Acute Myeloid Leukemia CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t miannu As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255585 0.44 SIGNOR-AML Acute Myeloid Leukemia CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 f irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well. SIGNOR-259195 0.427 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. SIGNOR-248283 0.632 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 t irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. SIGNOR-255700 0.2 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 factor protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT RARA factor protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255933 0.458 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 10090 BTO:0001516 14981546 t These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261522 0.448 SIGNOR-AML Acute Myeloid Leukemia SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22101255 f miannu Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli. SIGNOR-177485 0.2 SIGNOR-AML Acute Myeloid Leukemia RARA factor protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002136 11090075 t miannu RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα. SIGNOR-249636 0.247 SIGNOR-AML Acute Myeloid Leukemia 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 SIGNOR-AML Acute Myeloid Leukemia BAD protein Q92934 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256260 0.7 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 factor protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001412 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255749 0.2 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29967380 t miannu Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. SIGNOR-260119 0.309 SIGNOR-AML Acute Myeloid Leukemia EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-252671 0.772 SIGNOR-AML Acute Myeloid Leukemia JUN factor protein P05412 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-255660 0.577 SIGNOR-AML Acute Myeloid Leukemia MEIS1 factor protein O00470 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 0.2 SIGNOR-AML Acute Myeloid Leukemia PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AML Acute Myeloid Leukemia AMPK complex SIGNOR-C15 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252880 0.396 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.371 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT hsa-mir-223 mirna URS000037EC34_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 f miannu We could show that STAT5 is involved in miR-155 induction. STAT5 knockdown in FLT3-ITD model systems reduced miR-155 expression in vitro and in vivo. In silico analyses predicted an STAT binding site in the miR-155 promoter. SIGNOR-255817 0.4 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation. SIGNOR-255812 0.2 SIGNOR-AML Acute Myeloid Leukemia CCNA1 protein P78396 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation.  SIGNOR-255734 0.7 SIGNOR-AML Acute Myeloid Leukemia BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-AML Acute Myeloid Leukemia CEBPA factor protein P49715 UNIPROT SOX4 factor protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.396 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-AML Acute Myeloid Leukemia PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AML Acute Myeloid Leukemia NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates activity 9606 28213513 f Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential, SIGNOR-256307 0.375 SIGNOR-AML Acute Myeloid Leukemia TWIST1 factor protein Q15672 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255887 0.4 SIGNOR-AML Acute Myeloid Leukemia HES1 factor protein Q14469 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25234168 t We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. SIGNOR-261563 0.2 SIGNOR-AML Acute Myeloid Leukemia SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR KIT receptor protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29236325 f irozzo We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. SIGNOR-255699 0.2 SIGNOR-AML Acute Myeloid Leukemia CEBPA factor protein P49715 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14592841 t Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD SIGNOR-261531 0.549 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23817177 f irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255709 0.675 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 30552988 f miannu Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. SIGNOR-260132 0.298 SIGNOR-AML Acute Myeloid Leukemia CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110908 0.365 SIGNOR-AML Acute Myeloid Leukemia NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 26055960 f miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. SIGNOR-255802 0.4 SIGNOR-AML Acute Myeloid Leukemia glucose extracellular chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 10090 BTO:0000222 18477450 f Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). SIGNOR-256137 0.8 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 factor protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-244259 0.2 SIGNOR-AML Acute Myeloid Leukemia FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SIGNOR-AML Acute Myeloid Leukemia NOTCH1 protein P46531 UNIPROT HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 f lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. SIGNOR-183507 0.764 SIGNOR-AML Acute Myeloid Leukemia MEN1 protein O00255 UNIPROT MLL-ENL fusion protein SIGNOR-FP7 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255866 0.2 SIGNOR-AML Acute Myeloid Leukemia MIR1-1 mirna URS000075CF56_9606 RNAcentral PAX7 factor protein P23759 UNIPROT down-regulates quantity post transcriptional regulation 9606 24708856 t irozzo In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation SIGNOR-256124 0.4 SIGNOR-AML Acute Myeloid Leukemia EZH2 factor protein Q15910 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260068 0.41 SIGNOR-AML Acute Myeloid Leukemia midostaurin extracellular chemical CHEBI:63452 ChEBI FLT3 receptor protein P36888 UNIPROT down-regulates activity chemical inhibition -1 12124173 t PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors. SIGNOR-256308 0.8 SIGNOR-AML Acute Myeloid Leukemia TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0004479 29507660 f irozzo FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. SIGNOR-255733 0.428 SIGNOR-AML Acute Myeloid Leukemia AEP complex complex SIGNOR-C117 SIGNOR MEIS1 factor protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256144 0.397 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-AML Acute Myeloid Leukemia EP300 factor protein Q09472 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation SIGNOR-229780 0.7 SIGNOR-AML Acute Myeloid Leukemia TET2 protein Q6N021 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255704 0.7 SIGNOR-AML Acute Myeloid Leukemia CCNA1 protein P78396 UNIPROT WT1 factor protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19082485 f irozzo This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells. SIGNOR-255905 0.403 SIGNOR-AML Acute Myeloid Leukemia CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. SIGNOR-128445 0.679 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0001516 12796379 t FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. SIGNOR-261516 0.594 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176058 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251147 0.432 SIGNOR-AML Acute Myeloid Leukemia SPI1 factor protein P17947 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 SIGNOR-AML Acute Myeloid Leukemia PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9606 24252238 t miannu Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. SIGNOR-255679 0.487 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PTPRJ receptor protein Q12913 UNIPROT down-regulates activity 10090 22438257 f Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels. SIGNOR-261553 0.507 SIGNOR-AML Acute Myeloid Leukemia MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0005014 27856324 t irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255882 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251146 0.432 SIGNOR-AML Acute Myeloid Leukemia NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-AML Acute Myeloid Leukemia RXRA factor protein P19793 UNIPROT RARA factor protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16665 0.705 SIGNOR-AML Acute Myeloid Leukemia PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-AML Acute Myeloid Leukemia BAK1 protein Q16611 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261493 0.7 SIGNOR-AML Acute Myeloid Leukemia PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AML Acute Myeloid Leukemia MLL Fusion fusion protein SIGNOR-FP14 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260129 0.2 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 t miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 0.593 SIGNOR-AML Acute Myeloid Leukemia DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. SIGNOR-255714 0.7 SIGNOR-AML Acute Myeloid Leukemia IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 0.2 SIGNOR-AML Acute Myeloid Leukemia CEBPA factor protein P49715 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176054 0.2 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261551 0.641 SIGNOR-AML Acute Myeloid Leukemia PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.545 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0004760 15574429 f Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations SIGNOR-259950 0.374 SIGNOR-AML Acute Myeloid Leukemia PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-AML Acute Myeloid Leukemia FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252938 0.7 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT up-regulates activity 9534 8402896 f miannu BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. SIGNOR-261506 0.2 SIGNOR-AML Acute Myeloid Leukemia SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins SIGNOR-108499 0.581 SIGNOR-AML Acute Myeloid Leukemia FLT3LG extracellular protein P49771 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), SIGNOR-99750 0.88 SIGNOR-AML Acute Myeloid Leukemia BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 10080542 t gcesareni FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc SIGNOR-245060 0.587 SIGNOR-AML Acute Myeloid Leukemia SOX4 factor protein Q06945 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. SIGNOR-260133 0.7 SIGNOR-AML Acute Myeloid Leukemia PTEN protein P60484 UNIPROT STAT5A factor protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 t miannu The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166481 0.454 SIGNOR-AML Acute Myeloid Leukemia miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 factor protein P51608 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 23132946 f irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. SIGNOR-255884 0.4 SIGNOR-AML Acute Myeloid Leukemia ID1 factor protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; SIGNOR-255942 0.345 SIGNOR-AML Acute Myeloid Leukemia ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28516957 f miannu Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression SIGNOR-260074 0.347 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236298 0.2 SIGNOR-AML Acute Myeloid Leukemia CBLB protein Q13191 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates activity ubiquitination 10090 BTO:0001516 19276253 t miannu Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-260106 0.331 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-AML Acute Myeloid Leukemia PTEN protein P60484 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 31374292 t miannu PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. SIGNOR-260080 0.2 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. SIGNOR-255722 0.7 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR SPI1 factor protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000318 18519037 t We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1 SIGNOR-255671 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp) SIGNOR-153431 0.2 SIGNOR-AML Acute Myeloid Leukemia PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 10090 BTO:0003620 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling SIGNOR-248347 0.487 SIGNOR-AML Acute Myeloid Leukemia MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-AML Acute Myeloid Leukemia PTPN6 protein P29350 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation. SIGNOR-59965 0.426 SIGNOR-AML Acute Myeloid Leukemia MEIS1 factor protein O00470 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004052 14500898 t irozzo This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways. SIGNOR-256123 0.2 SIGNOR-AML Acute Myeloid Leukemia MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255869 0.2 SIGNOR-AML Acute Myeloid Leukemia CCND1 factor protein P24385 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 f andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. SIGNOR-255412 0.7 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255911 0.287 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 f Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD SIGNOR-261529 0.624 SIGNOR-AML Acute Myeloid Leukemia CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110912 0.365 SIGNOR-AML Acute Myeloid Leukemia CBL protein P22681 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0001516 19276253 t Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-255739 0.449 SIGNOR-AML Acute Myeloid Leukemia KLF2 factor protein Q9Y5W3 UNIPROT mir-143 mirna URS0000008A99_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 25477897 t miannu Overexpression of miR-155 leads to the activation of the PI3K-Akt pathway through negative regulation of Src Homology 2 domain-containing Inositol-5-Phosphatase (SHIP1). SIGNOR-255769 0.4 SIGNOR-AML Acute Myeloid Leukemia PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity binding 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260073 0.284 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0005248 8758906 t irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. SIGNOR-255999 0.2 SIGNOR-AML Acute Myeloid Leukemia PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT up-regulates quantity transcriptional regulation 9606 28213513 t We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. SIGNOR-256305 0.277 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001271 11283671 t apalma Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation. SIGNOR-255672 0.2 SIGNOR-AML Acute Myeloid Leukemia TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-AML Acute Myeloid Leukemia PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 factor protein P08047 UNIPROT up-regulates activity binding -1 18025157 t We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors. SIGNOR-255729 0.2 SIGNOR-AML Acute Myeloid Leukemia MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 factor protein Q09472 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C7 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-244239 0.2 SIGNOR-AML Acute Myeloid Leukemia DNMT3A protein Q9Y6K1 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24280869 f miannu HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A. SIGNOR-256128 0.349 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-AML Acute Myeloid Leukemia miR-155 mirna URS000062749E_9606 RNAcentral CEBPB factor protein P17676 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 25477897 t miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT3 SIGNOR-255795 0.4 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252833 0.909 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 0.2 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-AML Acute Myeloid Leukemia SP1 factor protein P08047 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255748 0.2 SIGNOR-AML Acute Myeloid Leukemia CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.757 SIGNOR-AML Acute Myeloid Leukemia FOXO factor proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260088 0.2 SIGNOR-AML Acute Myeloid Leukemia MLL-ENL fusion protein SIGNOR-FP7 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255878 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252837 0.909 SIGNOR-AML Acute Myeloid Leukemia RARA factor protein P10276 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16433 0.705 SIGNOR-AML Acute Myeloid Leukemia CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.909 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 26910834 f miannu RUNX1high was positively associated with miR-155, miR-125a, miR-99b, miR-133a, miR-130a, miR-25 and miR-92a-1. MiR-155 was previously found to function as an oncogene in CN-AML SIGNOR-255800 0.4 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 0.2 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML Acute Myeloid Leukemia NFY complex SIGNOR-C1 SIGNOR ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255746 0.274 SIGNOR-AML Acute Myeloid Leukemia diarsenic trioxide chemical CHEBI:30621 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 24344243 t ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein SIGNOR-259924 0.8 SIGNOR-AML Acute Myeloid Leukemia ASXL1 protein Q8IXJ9 UNIPROT RARA factor protein P10276 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255910 0.458 SIGNOR-AML Acute Myeloid Leukemia KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9534 BTO:0001538 7509796 t Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells SIGNOR-255949 0.708 SIGNOR-AML Acute Myeloid Leukemia STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-AML Acute Myeloid Leukemia BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-AML Acute Myeloid Leukemia PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-AML Acute Myeloid Leukemia BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18559972 f apalma In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors. SIGNOR-255698 0.268 SIGNOR-AML Acute Myeloid Leukemia MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT up-regulates activity binding 10090 BTO:0000944 12776190 t irozzo As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis. SIGNOR-256142 0.2 SIGNOR-AML Acute Myeloid Leukemia SIRT1 protein Q96EB6 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization deacetylation 9606 25280219 t SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites SIGNOR-261562 0.798 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246293 0.2 SIGNOR-AML Acute Myeloid Leukemia CEBPA factor protein P49715 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253830 0.506 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-AML Acute Myeloid Leukemia PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 0.2 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 f These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261521 0.298 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-244311 0.2 SIGNOR-AML Acute Myeloid Leukemia CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-AML Acute Myeloid Leukemia UBTF factor protein P17480 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. SIGNOR-260077 0.7 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-AML Acute Myeloid Leukemia RUNX1 factor protein Q01196 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 t miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements SIGNOR-260093 0.345 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 t lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 0.863 SIGNOR-AML Acute Myeloid Leukemia PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-AML Acute Myeloid Leukemia WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18192505 f Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity SIGNOR-261536 0.2 SIGNOR-AML Acute Myeloid Leukemia CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9834241 f miannu CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC. SIGNOR-256132 0.2 SIGNOR-AML Acute Myeloid Leukemia KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization transcriptional regulation 9606 31374292 t miannu The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. SIGNOR-260079 0.296 SIGNOR-AML Acute Myeloid Leukemia SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27524244 t miannu Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. SIGNOR-260076 0.285 SIGNOR-AML Acute Myeloid Leukemia MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR MECOM factor protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t irozzo We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-255858 0.2 SIGNOR-AML Acute Myeloid Leukemia PIM1 protein P11309 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates quantity phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. SIGNOR-259927 0.437 SIGNOR-AML Acute Myeloid Leukemia BCR-ABL fusion protein SIGNOR-FP6 SIGNOR STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 8642285 t irozzo Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. SIGNOR-255813 0.2 SIGNOR-AML Acute Myeloid Leukemia JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236290 0.2 SIGNOR-AML Acute Myeloid Leukemia SPI1 factor protein P17947 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 f miannu We showed a strong induction of miR-155 promoter activity by p65. We demonstrate that NF-κB (p65) directly binds to the miR-155 promoter in FLT3-ITD-associated MV4;11 cells. SIGNOR-255816 0.4 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.909 SIGNOR-AML Acute Myeloid Leukemia AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 f miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. SIGNOR-260096 0.547 SIGNOR-AML Acute Myeloid Leukemia PIM1 protein P11309 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 t FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells SIGNOR-261557 0.684 SIGNOR-AML Acute Myeloid Leukemia CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260072 0.382 SIGNOR-AML Acute Myeloid Leukemia PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 SIGNOR-AML Acute Myeloid Leukemia PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-AML Acute Myeloid Leukemia all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 19029980 t Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. SIGNOR-259926 0.8 SIGNOR-AML Acute Myeloid Leukemia MLL Fusion fusion protein SIGNOR-FP14 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t miannu Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-260131 0.2 SIGNOR-AML Acute Myeloid Leukemia GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-AML Acute Myeloid Leukemia KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity binding 9606 17259966 t miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 0.933 SIGNOR-AML Acute Myeloid Leukemia ETV6 factor protein P41212 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 SIGNOR-AML Acute Myeloid Leukemia NOTCH receptor proteinfamily SIGNOR-PF30 SIGNOR HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32195003 f Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR SIGNOR-261534 0.2 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.448 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 25477897 t miannu The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC SIGNOR-255796 0.4 SIGNOR-AML Acute Myeloid Leukemia TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-AML Acute Myeloid Leukemia AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates transcriptional regulation 9606 12091906 t apalma We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. SIGNOR-255677 0.2 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252834 0.909 SIGNOR-AML Acute Myeloid Leukemia CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 16103124 t lperfetto Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139653 0.495 SIGNOR-AML Acute Myeloid Leukemia RAD51 protein Q06609 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells SIGNOR-251508 0.7 SIGNOR-AML Acute Myeloid Leukemia MEN1 protein O00255 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 f irozzo We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells. SIGNOR-255895 0.7 SIGNOR-AML Acute Myeloid Leukemia FLT3LG extracellular protein P49771 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates binding 9606 10080542 t gcesareni Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1 SIGNOR-65564 0.88 SIGNOR-AML Acute Myeloid Leukemia NPM1 protein P06748 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.363 SIGNOR-AML Acute Myeloid Leukemia STAT5A factor protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261552 0.268 SIGNOR-AML Acute Myeloid Leukemia AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.909 SIGNOR-AML Acute Myeloid Leukemia BCOR protein Q6W2J9 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256010 0.7 SIGNOR-AML Acute Myeloid Leukemia FLT3 receptor protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 BTO:0001516 23246379 f miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-260083 0.537 SIGNOR-AML Acute Myeloid Leukemia CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 f miannu In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells SIGNOR-255736 0.7 SIGNOR-AML Acute Myeloid Leukemia TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-AML Acute Myeloid Leukemia NCOR2 factor protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t Ncor2 is a Skip corepressor gcesareni Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt. SIGNOR-74227 0.57 SIGNOR-AML Acute Myeloid Leukemia ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-AML Acute Myeloid Leukemia KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. SIGNOR-21193 0.933 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates transcriptional regulation 9606 12091906 t apalma We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. SIGNOR-255677 0.2 SIGNOR-AML1-ETO AML1-ETO in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML1-ETO AML1-ETO in AML PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 10090 BTO:0003620 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling SIGNOR-248347 0.487 SIGNOR-AML1-ETO AML1-ETO in AML SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27524244 t miannu Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. SIGNOR-260076 0.285 SIGNOR-AML1-ETO AML1-ETO in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-AML1-ETO AML1-ETO in AML TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001271 11283671 t apalma Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation. SIGNOR-255672 0.2 SIGNOR-AML1-ETO AML1-ETO in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML1-ETO AML1-ETO in AML CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.757 SIGNOR-AML1-ETO AML1-ETO in AML CEBPA factor protein P49715 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253830 0.506 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR SPI1 factor protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000318 18519037 t We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1 SIGNOR-255671 0.2 SIGNOR-AML1-ETO AML1-ETO in AML SPI1 factor protein P17947 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 SIGNOR-AML1-ETO AML1-ETO in AML SOX4 factor protein Q06945 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors. SIGNOR-255676 0.7 SIGNOR-AML1-ETO AML1-ETO in AML AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-AML1-ETO AML1-ETO in AML PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9606 24252238 t miannu Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. SIGNOR-255679 0.487 SIGNOR-AML1-ETO AML1-ETO in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JUN factor protein P05412 UNIPROT down-regulates activity binding 9606 BTO:0004136 12393465 t RUNX1-RUNX1T1 fusion protein (AML-ETO) apalma Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun. SIGNOR-255670 0.2 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTPRC receptor protein P08575 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-255686 0.2 SIGNOR-AML1-ETO AML1-ETO in AML PTGS2 protein P35354 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification 9606 16540375 t Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES) SIGNOR-255684 0.8 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 t irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. SIGNOR-255700 0.2 SIGNOR-AML1-ETO AML1-ETO in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML1-ETO AML1-ETO in AML TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-AML1-ETO AML1-ETO in AML SOX4 factor protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0003104 24970928 t irozzo The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes. SIGNOR-256139 0.576 SIGNOR-AML1-ETO AML1-ETO in AML prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 f apalma Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255685 0.8 SIGNOR-AML1-ETO AML1-ETO in AML FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-AML1-ETO AML1-ETO in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-AML1-ETO AML1-ETO in AML PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248349 0.487 SIGNOR-AML1-ETO AML1-ETO in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML1-ETO AML1-ETO in AML PTPRC receptor protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248348 0.487 SIGNOR-AML1-ETO AML1-ETO in AML CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004850 23645839 f miannu AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. SIGNOR-255683 0.2 SIGNOR-AML1-ETO AML1-ETO in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-260120 0.2 SIGNOR-AML1-ETO AML1-ETO in AML CEBPA factor protein P49715 UNIPROT SOX4 factor protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.396 SIGNOR-AML1-ETO AML1-ETO in AML CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-AML1-ETO AML1-ETO in AML JUN factor protein P05412 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-255660 0.577 SIGNOR-AML-ASXL1 ASXL1 in AML RXRA factor protein P19793 UNIPROT RARA factor protein P10276 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16665 0.705 SIGNOR-AML-ASXL1 ASXL1 in AML PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-AML-ASXL1 ASXL1 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 factor protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-244259 0.2 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT RARA factor protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255933 0.458 SIGNOR-AML-ASXL1 ASXL1 in AML CCNA1 protein P78396 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation.  SIGNOR-255734 0.7 SIGNOR-AML-ASXL1 ASXL1 in AML BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0002181 17379597 t irozzo BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. SIGNOR-259193 0.452 SIGNOR-AML-ASXL1 ASXL1 in AML RARA factor protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002136 11090075 t miannu RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα. SIGNOR-249636 0.247 SIGNOR-AML-ASXL1 ASXL1 in AML NCOA1 factor protein Q15788 UNIPROT RARA factor protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255932 0.691 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates activity binding 9606 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255931 0.29 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22897849 f miannu ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR SIGNOR-256127 0.448 SIGNOR-AML-ASXL1 ASXL1 in AML CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 f irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well. SIGNOR-259195 0.427 SIGNOR-AML-ASXL1 ASXL1 in AML NCOA1 factor protein Q15788 UNIPROT ASXL1 protein Q8IXJ9 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255924 0.29 SIGNOR-AML-ASXL1 ASXL1 in AML EZH2 factor protein Q15910 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260068 0.41 SIGNOR-AML-ASXL1 ASXL1 in AML HOXA9 factor protein P31269 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255864 0.7 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29967380 t miannu Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. SIGNOR-260119 0.309 SIGNOR-AML-ASXL1 ASXL1 in AML RARA factor protein P10276 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16433 0.705 SIGNOR-AML-ASXL1 ASXL1 in AML CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT RARA factor protein P10276 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255910 0.458 SIGNOR-AML-ASXL1 ASXL1 in AML ASXL1 protein Q8IXJ9 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255911 0.287 SIGNOR-AML-ASXL1 ASXL1 in AML FLT3 receptor protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 BTO:0001516 23246379 f miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-260083 0.537 SIGNOR-AML-BCRABL BCR-ABL in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246293 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252833 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-244311 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0005248 8758906 t irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. SIGNOR-255999 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML PTEN protein P60484 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 31374292 t miannu PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. SIGNOR-260080 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization transcriptional regulation 9606 31374292 t miannu The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. SIGNOR-260079 0.296 SIGNOR-AML-BCRABL BCR-ABL in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004052 14500898 t irozzo This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways. SIGNOR-256123 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252837 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 8642285 t irozzo Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. SIGNOR-255813 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-AML-BCRABL BCR-ABL in AML CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 f apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255586 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-AML-BCRABL BCR-ABL in AML BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.641 SIGNOR-AML-BCRABL BCR-ABL in AML CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t miannu As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways SIGNOR-255585 0.44 SIGNOR-AML-BCRABL BCR-ABL in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-AML-BCRABL BCR-ABL in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.785 SIGNOR-AML-BCRABL BCR-ABL in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation. SIGNOR-255812 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-AML-BCRABL BCR-ABL in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AML-BCRABL BCR-ABL in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-AML-BCRABL BCR-ABL in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 t irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. SIGNOR-255820 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-AML-BCRABL BCR-ABL in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-AML-BCRABL BCR-ABL in AML JAK2 protein O60674 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization binding 10090 12370803 t irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255810 0.47 SIGNOR-AML-BCRABL BCR-ABL in AML JAK2 protein O60674 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12370803 f irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  SIGNOR-255811 0.47 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-AML-BCRABL BCR-ABL in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-BCRABL BCR-ABL in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246285 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246281 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB receptor complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity SIGNOR-255584 0.565 SIGNOR-AML-BCRABL BCR-ABL in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 t gcesareni BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation SIGNOR-248199 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-AML-BCRABL BCR-ABL in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246289 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-AML-BCRABL BCR-ABL in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247146 0.2 SIGNOR-AML-BCRABL BCR-ABL in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-AML-BCRABL BCR-ABL in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.909 SIGNOR-AML-DNMT3A DNMT3A in AML DNMT3A protein Q9Y6K1 UNIPROT MEIS1 factor protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 f miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. SIGNOR-256125 0.338 SIGNOR-AML-DNMT3A DNMT3A in AML DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-255809 0.393 SIGNOR-AML-DNMT3A DNMT3A in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-AML-DNMT3A DNMT3A in AML DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. SIGNOR-255714 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML DNMT3A protein Q9Y6K1 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255808 0.483 SIGNOR-AML-DNMT3A DNMT3A in AML TET2 protein Q6N021 UNIPROT WT1 factor protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.467 SIGNOR-AML-DNMT3A DNMT3A in AML FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-AML-DNMT3A DNMT3A in AML FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243545 0.754 SIGNOR-AML-DNMT3A DNMT3A in AML IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 SIGNOR-AML-DNMT3A DNMT3A in AML HOXA9 factor protein P31269 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.647 SIGNOR-AML-DNMT3A DNMT3A in AML NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-AML-DNMT3A DNMT3A in AML NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-AML-DNMT3A DNMT3A in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-AML-DNMT3A DNMT3A in AML MEIS1 factor protein O00470 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 SIGNOR-AML-DNMT3A DNMT3A in AML IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 SIGNOR-AML-DNMT3A DNMT3A in AML MEIS1 factor protein O00470 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-AML-DNMT3A DNMT3A in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-AML-DNMT3A DNMT3A in AML NPM1 protein P06748 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.363 SIGNOR-AML-DNMT3A DNMT3A in AML CCND1 factor protein P24385 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 f andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. SIGNOR-255412 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML DNMT3A protein Q9Y6K1 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24280869 f miannu HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A. SIGNOR-256128 0.349 SIGNOR-AML-DNMT3A DNMT3A in AML TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-AML-DNMT3A DNMT3A in AML CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.757 SIGNOR-AML-DNMT3A DNMT3A in AML MEIS1 factor protein O00470 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 SIGNOR-AML-DNMT3A DNMT3A in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-AML-FLT3 FLT3 in AML diarsenic trioxide chemical CHEBI:30621 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 24344243 t ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein SIGNOR-259924 0.8 SIGNOR-AML-FLT3 FLT3 in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 t lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 0.863 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 10080542 t gcesareni FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc SIGNOR-245060 0.587 SIGNOR-AML-FLT3 FLT3 in AML CBLB protein Q13191 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates activity ubiquitination 10090 BTO:0001516 19276253 t miannu Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-260106 0.331 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.909 SIGNOR-AML-FLT3 FLT3 in AML PIM1 protein P11309 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates quantity phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. SIGNOR-259927 0.437 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 factor protein Q09472 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C7 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-244239 0.2 SIGNOR-AML-FLT3 FLT3 in AML FLT3LG extracellular protein P49771 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), SIGNOR-99750 0.88 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.909 SIGNOR-AML-FLT3 FLT3 in AML NFY complex SIGNOR-C1 SIGNOR ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255746 0.274 SIGNOR-AML-FLT3 FLT3 in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML-FLT3 FLT3 in AML ID1 factor protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; SIGNOR-255942 0.345 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252834 0.909 SIGNOR-AML-FLT3 FLT3 in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.909 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252837 0.909 SIGNOR-AML-FLT3 FLT3 in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18559972 f apalma In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors. SIGNOR-255698 0.268 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-AML-FLT3 FLT3 in AML FLT3LG extracellular protein P49771 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates binding 9606 10080542 t gcesareni Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1 SIGNOR-65564 0.88 SIGNOR-AML-FLT3 FLT3 in AML SP1 factor protein P08047 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255748 0.2 SIGNOR-AML-FLT3 FLT3 in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-AML-FLT3 FLT3 in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 factor protein P08047 UNIPROT up-regulates activity binding -1 18025157 t We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors. SIGNOR-255729 0.2 SIGNOR-AML-FLT3 FLT3 in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252833 0.909 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-AML-FLT3 FLT3 in AML RUNX1 factor protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT up-regulates quantity transcriptional regulation 9606 28213513 t We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. SIGNOR-256305 0.277 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-AML-FLT3 FLT3 in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-AML-FLT3 FLT3 in AML all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 19029980 t Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. SIGNOR-259926 0.8 SIGNOR-AML-FLT3 FLT3 in AML CBL protein P22681 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0001516 19276253 t Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. SIGNOR-255739 0.449 SIGNOR-AML-FLT3 FLT3 in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates activity 9606 28213513 f Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential, SIGNOR-256307 0.375 SIGNOR-AML-FLT3 FLT3 in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-AML-FLT3 FLT3 in AML midostaurin extracellular chemical CHEBI:63452 ChEBI FLT3 receptor protein P36888 UNIPROT down-regulates activity chemical inhibition -1 12124173 t PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors. SIGNOR-256308 0.8 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.909 SIGNOR-AML-FLT3 FLT3 in AML PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255982 0.646 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.909 SIGNOR-AML-FLT3 FLT3 in AML CCNA1 protein P78396 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 f miannu SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation.  SIGNOR-255734 0.7 SIGNOR-AML-FLT3 FLT3 in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-AML-FLT3 FLT3 in AML SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-AML-FLT3 FLT3 in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-AML-FLT3 FLT3 in AML STAT5A factor protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0004479 29507660 f irozzo FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. SIGNOR-255733 0.428 SIGNOR-AML-FLT3 FLT3 in AML HHEX protein Q03014 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 BTO:0000089 26728554 f Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal. SIGNOR-256306 0.7 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SIGNOR-AML-FLT3 FLT3 in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.545 SIGNOR-AML-FLT3 FLT3 in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.909 SIGNOR-AML-FLT3 FLT3 in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19797526 f We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding. SIGNOR-255726 0.2 SIGNOR-AML-FLT3 FLT3 in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-AML-FLT3 FLT3 in AML GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. SIGNOR-114704 0.9 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-AML-FLT3 FLT3 in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-AML-FLT3 FLT3 in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 factor protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-244236 0.2 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.909 SIGNOR-AML-FLT3 FLT3 in AML AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.909 SIGNOR-AML-FLT3 FLT3 in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 factor protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001412 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255749 0.2 SIGNOR-AML-FLT3 FLT3 in AML KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-AML-FLT3 FLT3 in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SIGNOR-AML-FLT3 FLT3 in AML CEBPA factor protein P49715 UNIPROT SOX4 factor protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.396 SIGNOR-AML-FLT3 FLT3 in AML CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-AML-FLT3 FLT3 in AML PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9534 8943354 t Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 SIGNOR-248466 0.718 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-AML-FLT3 FLT3 in AML PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 f miannu The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-255732 0.7 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.371 SIGNOR-AML-FLT3 FLT3 in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AML-FLT3 FLT3 in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR NFY complex SIGNOR-C1 SIGNOR up-regulates activity binding 9606 BTO:0000972 18025157 t We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255747 0.2 SIGNOR-AML-FLT3 FLT3 in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-FLT3 FLT3 in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML-FLT3 FLT3 in AML SOX4 factor protein Q06945 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors. SIGNOR-255676 0.7 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 t miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. SIGNOR-260124 0.425 SIGNOR-AML-FLT3 FLT3 in AML KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-AML-FLT3 FLT3 in AML EP300 factor protein Q09472 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 f amattioni Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation SIGNOR-229780 0.7 SIGNOR-AML-FLT3 FLT3 in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AML-FLT3 FLT3 in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11090075 f Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins. SIGNOR-255725 0.2 SIGNOR-AML-FLT3 FLT3 in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML-FLT3 FLT3 in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252824 0.909 SIGNOR-AML-FLT3 FLT3 in AML GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0001516 23246379 t Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation SIGNOR-255946 0.341 SIGNOR-AML-FLT3 FLT3 in AML MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-AML-FLT3 FLT3 in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-AML-FLT3 FLT3 in AML SOX4 factor protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000038 17875931 t irozzo We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein. SIGNOR-256138 0.576 SIGNOR-AML-FLT3 FLT3 in AML FLT3 receptor protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0004760 15574429 f Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations SIGNOR-259950 0.374 SIGNOR-AML-FLT3 FLT3 in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM factor protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-260107 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. SIGNOR-251357 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 t Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction SIGNOR-251360 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. SIGNOR-255714 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML STAT5A factor protein P42229 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells SIGNOR-256583 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity SIGNOR-236506 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251359 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CCNA1 protein P78396 UNIPROT WT1 factor protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19082485 f irozzo This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells. SIGNOR-255905 0.403 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-252700 0.662 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML STAT5A factor protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity transcriptional regulation 9606 26059451 t … these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells SIGNOR-255631 0.334 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-260120 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 t miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-44557 0.865 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000830 15526160 t miannu Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase SIGNOR-254949 0.708 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-255809 0.393 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19797526 f We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding. SIGNOR-255726 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML NUP98 Fusion fusion protein SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32344427 f miannu NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition. SIGNOR-261505 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 BTO:0004136 10208431 t miannu The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex SIGNOR-260094 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 BTO:0000093 8415704 f miannu PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site SIGNOR-261507 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates activity 9606 11090075 t apalma We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway. SIGNOR-256373 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML DOT1L protein Q8TEK3 UNIPROT HOXA9 factor protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256141 0.466 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates activity binding 10090 BTO:0002882 26387755 t Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53. SIGNOR-255737 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MECOM factor protein Q03112 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 t irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. SIGNOR-255716 0.507 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176058 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-236502 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. SIGNOR-235885 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR KIT receptor protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29236325 f irozzo We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. SIGNOR-255699 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260129 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML WT1 factor protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23042785 t irozzo Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. SIGNOR-255904 0.394 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176054 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 t irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. SIGNOR-255700 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. SIGNOR-260130 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CEBPA factor protein P49715 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CDK6 protein Q00534 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-169334 0.593 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CEBPA factor protein P49715 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001056 11283671 t apalma Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells. SIGNOR-255673 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 f apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. SIGNOR-255577 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation. SIGNOR-255812 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML HOXA9 factor protein P31269 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255864 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PTEN protein P60484 UNIPROT STAT5A factor protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 t miannu The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166481 0.454 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML DNMT3A protein Q9Y6K1 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24280869 f miannu HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A. SIGNOR-256128 0.349 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML NPM1 protein P06748 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.363 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236298 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PTEN protein P60484 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 31374292 t miannu PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. SIGNOR-260080 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp) SIGNOR-153431 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 t 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. SIGNOR-235910 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 t Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity SIGNOR-251358 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 t lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein SIGNOR-249507 0.863 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9834241 f miannu CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC. SIGNOR-256132 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236290 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates transcriptional regulation 9606 12091906 t apalma We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. SIGNOR-255677 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML MEN1 protein O00255 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 f irozzo We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells. SIGNOR-255895 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML BCR-ABL fusion protein SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT up-regulates activity 9534 8402896 f miannu BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. SIGNOR-261506 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA factor protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001271 11283671 t apalma Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation. SIGNOR-255672 0.2 SIGNOR-AML-FusionProteins Onco-fusion proteins in AML PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. SIGNOR-255722 0.7 SIGNOR-AML-IDH-TET AML-IDH/TET WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-AML-IDH-TET AML-IDH/TET 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 SIGNOR-AML-IDH-TET AML-IDH/TET IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 SIGNOR-AML-IDH-TET AML-IDH/TET IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 SIGNOR-AML-IDH-TET AML-IDH/TET TET2 protein Q6N021 UNIPROT WT1 factor protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.467 SIGNOR-AML-IDH_TET IDH-TET in AML IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 SIGNOR-AML-IDH_TET IDH-TET in AML CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 t gcesareni Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139649 0.495 SIGNOR-AML-IDH_TET IDH-TET in AML AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001412 31900833 t miannu Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. SIGNOR-260097 0.2 SIGNOR-AML-IDH_TET IDH-TET in AML TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-AML-IDH_TET IDH-TET in AML AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256135 0.2 SIGNOR-AML-IDH_TET IDH-TET in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML-IDH_TET IDH-TET in AML glucose extracellular chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 10090 BTO:0000222 18477450 f Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). SIGNOR-256137 0.8 SIGNOR-AML-IDH_TET IDH-TET in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-252928 0.2 SIGNOR-AML-IDH_TET IDH-TET in AML 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 SIGNOR-AML-IDH_TET IDH-TET in AML TET2 protein Q6N021 UNIPROT WT1 factor protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.467 SIGNOR-AML-IDH_TET IDH-TET in AML KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation. SIGNOR-170594 0.484 SIGNOR-AML-IDH_TET IDH-TET in AML IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 SIGNOR-AML-IDH_TET IDH-TET in AML AMPK complex SIGNOR-C15 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252880 0.396 SIGNOR-AML-IDH_TET IDH-TET in AML CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. SIGNOR-128445 0.679 SIGNOR-AML-IDH_TET IDH-TET in AML ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28516957 f miannu Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression SIGNOR-260074 0.347 SIGNOR-AML-IDH_TET IDH-TET in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML-IDH_TET IDH-TET in AML WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-AML-IDH_TET IDH-TET in AML CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 16103124 t lperfetto Moreover, app stabilized tip60 through cdk-dependent phosphorylation SIGNOR-139653 0.495 SIGNOR-AML-IDH_TET IDH-TET in AML AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 f miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. SIGNOR-260096 0.547 SIGNOR-AML-IDH_TET IDH-TET in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260088 0.2 SIGNOR-AML-IDH_TET IDH-TET in AML SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27524244 t miannu Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. SIGNOR-260076 0.285 SIGNOR-AML-KIT KIT in AML KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9534 BTO:0001538 7509796 t Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells SIGNOR-255949 0.708 SIGNOR-AML-KIT KIT in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-AML-KIT KIT in AML CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110912 0.365 SIGNOR-AML-KIT KIT in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-AML-KIT KIT in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-AML-KIT KIT in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-AML-KIT KIT in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML-KIT KIT in AML RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML-KIT KIT in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AML-KIT KIT in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-AML-KIT KIT in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AML-KIT KIT in AML ETV6 factor protein P41212 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 SIGNOR-AML-KIT KIT in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-AML-KIT KIT in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 f miannu In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells SIGNOR-255736 0.7 SIGNOR-AML-KIT KIT in AML KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity binding 9606 17259966 t miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 0.933 SIGNOR-AML-KIT KIT in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-AML-KIT KIT in AML TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-AML-KIT KIT in AML CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260072 0.382 SIGNOR-AML-KIT KIT in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML-KIT KIT in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-AML-KIT KIT in AML PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity binding 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260073 0.284 SIGNOR-AML-KIT KIT in AML STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 SIGNOR-AML-KIT KIT in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-AML-KIT KIT in AML KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. SIGNOR-21193 0.933 SIGNOR-AML-KIT KIT in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9834241 f miannu CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC. SIGNOR-256132 0.2 SIGNOR-AML-KIT KIT in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML-KIT KIT in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 factor protein P04637 UNIPROT down-regulates activity binding 10090 BTO:0002882 26387755 t Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53. SIGNOR-255737 0.2 SIGNOR-AML-KIT KIT in AML MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-AML-KIT KIT in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AML-KIT KIT in AML KIT receptor protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 t miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 0.593 SIGNOR-AML-KIT KIT in AML PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-AML-KIT KIT in AML KIT receptor protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. SIGNOR-248283 0.632 SIGNOR-AML-KIT KIT in AML CBLB protein Q13191 UNIPROT KIT receptor protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260105 0.332 SIGNOR-AML-KIT KIT in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-AML-KIT KIT in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-AML-KIT KIT in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-AML-KIT KIT in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 factor protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 SIGNOR-AML-KIT KIT in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-AML-KIT KIT in AML SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-AML-KIT KIT in AML CBL protein P22681 UNIPROT KIT receptor protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 t miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. SIGNOR-260104 0.597 SIGNOR-AML-KIT KIT in AML SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22101255 f miannu Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli. SIGNOR-177485 0.2 SIGNOR-AML-KIT KIT in AML NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-AML-KIT KIT in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML-KIT KIT in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-KIT KIT in AML STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-AML-KIT KIT in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AML-KIT KIT in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-AML-KIT KIT in AML CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 SIGNOR-AML-KIT KIT in AML JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.813 SIGNOR-AML-KIT KIT in AML BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-AML-KIT KIT in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-AML-KIT KIT in AML AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-AML-KIT KIT in AML JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-AML-KIT KIT in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AML-KIT KIT in AML KIT receptor protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 22806893 t irozzo SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation. SIGNOR-256140 0.669 SIGNOR-AML-KIT KIT in AML GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. SIGNOR-114704 0.9 SIGNOR-AML-KIT KIT in AML CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. SIGNOR-110908 0.365 SIGNOR-AML-KIT KIT in AML KIT receptor protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000141 18179858 t irozzo KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models. SIGNOR-256121 0.708 SIGNOR-AML-KIT KIT in AML SH2B3 protein Q9UQQ2 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 10090 BTO:0002882 18618018 t miannu we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions. SIGNOR-260075 0.631 SIGNOR-AML-KIT KIT in AML GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-AML-KIT KIT in AML PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255754 0.661 SIGNOR-AML_miRNA miRNA in AML SPI1 factor protein P17947 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 SIGNOR-AML_miRNA miRNA in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-AML_miRNA miRNA in AML AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-AML_miRNA miRNA in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-AML_miRNA miRNA in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251146 0.432 SIGNOR-AML_miRNA miRNA in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-AML_miRNA miRNA in AML NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 26055960 f miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. SIGNOR-255802 0.4 SIGNOR-AML_miRNA miRNA in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AML_miRNA miRNA in AML TET2 protein Q6N021 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255704 0.7 SIGNOR-AML_miRNA miRNA in AML SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t gcesareni The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-66949 0.681 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251148 0.432 SIGNOR-AML_miRNA miRNA in AML miR-155 mirna URS000062749E_9606 RNAcentral FOS factor protein P01100 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 24708856 t miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. SIGNOR-255766 0.4 SIGNOR-AML_miRNA miRNA in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-AML_miRNA miRNA in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AML_miRNA miRNA in AML MIR1-1 mirna URS000075CF56_9606 RNAcentral PAX7 factor protein P23759 UNIPROT down-regulates quantity post transcriptional regulation 9606 24708856 t irozzo In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation SIGNOR-256124 0.4 SIGNOR-AML_miRNA miRNA in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-AML_miRNA miRNA in AML miR-199a mirna URS0000759977_9606 RNAcentral MTOR protein P42345 UNIPROT up-regulates activity 9606 26055960 t miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. SIGNOR-255803 0.4 SIGNOR-AML_miRNA miRNA in AML SPI1 factor protein P17947 UNIPROT miR-338 mirna URS000075E706_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255886 0.4 SIGNOR-AML_miRNA miRNA in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML_miRNA miRNA in AML DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 f irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. SIGNOR-255714 0.7 SIGNOR-AML_miRNA miRNA in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-AML_miRNA miRNA in AML INPP5D protein Q92835 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 12421919 t gcesareni Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten SIGNOR-252428 0.8 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SIGNOR-251147 0.432 SIGNOR-AML_miRNA miRNA in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-AML_miRNA miRNA in AML MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-AML_miRNA miRNA in AML TWIST1 factor protein Q15672 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255887 0.4 SIGNOR-AML_miRNA miRNA in AML MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 extracellular protein P05019 UNIPROT down-regulates quantity post transcriptional regulation 9606 25477897 t miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1 SIGNOR-255793 0.4 SIGNOR-AML_miRNA miRNA in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AML_miRNA miRNA in AML RUNX1 factor protein Q01196 UNIPROT hsa-mir-223 mirna URS000037EC34_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 f miannu We could show that STAT5 is involved in miR-155 induction. STAT5 knockdown in FLT3-ITD model systems reduced miR-155 expression in vitro and in vivo. In silico analyses predicted an STAT binding site in the miR-155 promoter. SIGNOR-255817 0.4 SIGNOR-AML_miRNA miRNA in AML STAT5A factor protein P42229 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 f irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. SIGNOR-255885 0.4 SIGNOR-AML_miRNA miRNA in AML TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-AML_miRNA miRNA in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-AML_miRNA miRNA in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.448 SIGNOR-AML_miRNA miRNA in AML SP1 factor protein P08047 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255748 0.2 SIGNOR-AML_miRNA miRNA in AML RUNX1 factor protein Q01196 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 26910834 f miannu RUNX1high was positively associated with miR-155, miR-125a, miR-99b, miR-133a, miR-130a, miR-25 and miR-92a-1. MiR-155 was previously found to function as an oncogene in CN-AML SIGNOR-255800 0.4 SIGNOR-AML_miRNA miRNA in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-AML_miRNA miRNA in AML miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 factor protein P51608 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 23132946 f irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. SIGNOR-255884 0.4 SIGNOR-AML_miRNA miRNA in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AML_miRNA miRNA in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML_miRNA miRNA in AML KLF2 factor protein Q9Y5W3 UNIPROT mir-143 mirna URS0000008A99_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 25477897 t miannu Overexpression of miR-155 leads to the activation of the PI3K-Akt pathway through negative regulation of Src Homology 2 domain-containing Inositol-5-Phosphatase (SHIP1). SIGNOR-255769 0.4 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 25477897 t miannu The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC SIGNOR-255796 0.4 SIGNOR-AML_miRNA miRNA in AML RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML_miRNA miRNA in AML PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-AML_miRNA miRNA in AML SPI1 factor protein P17947 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 f miannu We showed a strong induction of miR-155 promoter activity by p65. We demonstrate that NF-κB (p65) directly binds to the miR-155 promoter in FLT3-ITD-associated MV4;11 cells. SIGNOR-255816 0.4 SIGNOR-AML_miRNA miRNA in AML TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-AML_miRNA miRNA in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML_miRNA miRNA in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AML_miRNA miRNA in AML PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-AML_miRNA miRNA in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-AML_miRNA miRNA in AML ID1 factor protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 t apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; SIGNOR-255942 0.345 SIGNOR-AML_miRNA miRNA in AML miR-155 mirna URS000062749E_9606 RNAcentral CEBPB factor protein P17676 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 25477897 t miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT3 SIGNOR-255795 0.4 SIGNOR-AML_miRNA miRNA in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML_miRNA miRNA in AML FLT3 receptor protein P36888 UNIPROT ID1 factor protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18559972 f apalma In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors. SIGNOR-255698 0.268 SIGNOR-AML-MLL MLL fusion protein in AML RUNX1 factor protein Q01196 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 t miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements SIGNOR-260093 0.345 SIGNOR-AML-MLL MLL fusion protein in AML BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-AML-MLL MLL fusion protein in AML MLL-ENL fusion protein SIGNOR-FP7 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255878 0.2 SIGNOR-AML-MLL MLL fusion protein in AML UBTF factor protein P17480 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 f miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. SIGNOR-260077 0.7 SIGNOR-AML-MLL MLL fusion protein in AML RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML-MLL MLL fusion protein in AML BCOR protein Q6W2J9 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256010 0.7 SIGNOR-AML-MLL MLL fusion protein in AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML-MLL MLL fusion protein in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t miannu Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-260131 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR MECOM factor protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t irozzo We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-255858 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MEIS1 factor protein O00470 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255869 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT up-regulates activity binding 10090 BTO:0000944 12776190 t irozzo As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis. SIGNOR-256142 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255876 0.2 SIGNOR-AML-MLL MLL fusion protein in AML BCOR protein Q6W2J9 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256011 0.7 SIGNOR-AML-MLL MLL fusion protein in AML MLL-ENL fusion protein SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255870 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-MLL MLL fusion protein in AML AEP complex complex SIGNOR-C117 SIGNOR HOXA9 factor protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-255879 0.423 SIGNOR-AML-MLL MLL fusion protein in AML MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w SIGNOR-151787 0.718 SIGNOR-AML-MLL MLL fusion protein in AML MEN1 protein O00255 UNIPROT MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255868 0.2 SIGNOR-AML-MLL MLL fusion protein in AML DOT1L protein Q8TEK3 UNIPROT HOXA9 factor protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256141 0.466 SIGNOR-AML-MLL MLL fusion protein in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 SIGNOR-AML-MLL MLL fusion protein in AML AEP complex complex SIGNOR-C117 SIGNOR MEIS1 factor protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256144 0.397 SIGNOR-AML-MLL MLL fusion protein in AML MEN1 protein O00255 UNIPROT MLL-ENL fusion protein SIGNOR-FP7 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255866 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255867 0.2 SIGNOR-AML-MLL MLL fusion protein in AML RUNX1 factor protein Q01196 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23817177 f irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255709 0.675 SIGNOR-AML-MLL MLL fusion protein in AML RAD21 protein O60216 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 t miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells SIGNOR-259973 0.29 SIGNOR-AML-MLL MLL fusion protein in AML DOT1L protein Q8TEK3 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255880 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM factor protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-260107 0.2 SIGNOR-AML-MLL MLL fusion protein in AML SPI1 factor protein P17947 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 SIGNOR-AML-MLL MLL fusion protein in AML DOT1L protein Q8TEK3 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256143 0.417 SIGNOR-AML-MLL MLL fusion protein in AML MLL Fusion fusion protein SIGNOR-FP14 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260129 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260128 0.2 SIGNOR-AML-MLL MLL fusion protein in AML BAK1 protein Q16611 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261493 0.7 SIGNOR-AML-MLL MLL fusion protein in AML DOT1L protein Q8TEK3 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0001939 26199140 t 1 miannu Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1 SIGNOR-239362 0.345 SIGNOR-AML-MLL MLL fusion protein in AML HOXA9 factor protein P31269 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.647 SIGNOR-AML-MLL MLL fusion protein in AML MEIS1 factor protein O00470 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260126 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0005014 27856324 t irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255882 0.2 SIGNOR-AML-MLL MLL fusion protein in AML PHF6 protein Q8IWS0 UNIPROT UBTF factor protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf SIGNOR-200133 0.285 SIGNOR-AML-MLL MLL fusion protein in AML DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255881 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260127 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MECOM factor protein Q03112 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 t irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. SIGNOR-255716 0.507 SIGNOR-AML-MLL MLL fusion protein in AML MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax SIGNOR-149774 0.603 SIGNOR-AML-MLL MLL fusion protein in AML MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. SIGNOR-260130 0.2 SIGNOR-AML-MLL MLL fusion protein in AML MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255877 0.2 SIGNOR-AML-NP1 NPM1 in AML TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-AML-NP1 NPM1 in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-AML-NP1 NPM1 in AML NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-AML-NP1 NPM1 in AML MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-AML-NP1 NPM1 in AML NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-AML-NP1 NPM1 in AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML-NP1 NPM1 in AML FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-AML-NP1 NPM1 in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-AML-NP1 NPM1 in AML CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.757 SIGNOR-AML-NP1 NPM1 in AML MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-AML-NP1 NPM1 in AML CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-AML-NP1 NPM1 in AML TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-AML-NP1 NPM1 in AML TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CBFB protein Q13951 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 11179217 t irozzo We observed previously that the RUNX proteins are susceptible to proteolytic degradation (Ogawa et al., 1993b). In this study, we show that the ubiquitin‚proteasome system is largely responsible for this degradation. We also show that when PEBP2Œ≤ dimerizes with RUNX it inhibits the ubiquitylation of RUNX, which is necessary for the protein to be targeted for proteolysis by the proteasome. SIGNOR-255712 0.838 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KLF1 factor protein Q13351 UNIPROT FLI1 factor protein Q01543 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction. SIGNOR-256046 0.379 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 factor protein P23769 UNIPROT GATA1 factor protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 f irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. SIGNOR-256056 0.415 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT KLF1 factor protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 f irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. SIGNOR-256051 0.524 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 factor protein P11161 UNIPROT Monocyte_differentiation phenotypesList phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes. SIGNOR-256089 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT GATA2 factor protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12433372 f irozzo Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. SIGNOR-256069 0.602 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl MAPK14 protein Q16539 UNIPROT GATA2 factor protein P23769 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 25056917 t P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes. SIGNOR-259946 0.274 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT TAL1 factor protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7632958 f irozzo Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators. SIGNOR-256047 0.777 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 factor protein P11161 UNIPROT GFI1 factor protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256041 0.316 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 factor protein Q01543 UNIPROT Megakaryocyte_differentiation phenotypesList phenotype SIGNOR-PH103 SIGNOR up-regulates 9606 BTO:0000565 28052010 f irozzo The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. SIGNOR-256087 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 factor protein Q99684 UNIPROT EGR2 factor protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f irozzo Importantly, overexpression of Gfi-1 in these cells resulted in the attenuation of both Egr-1 and Egr-2 expression, but not Nab-2. SIGNOR-256133 0.316 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CEBPA factor protein P49715 UNIPROT GFI1 factor protein Q99684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20924107 f irozzo We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1. SIGNOR-256068 0.387 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 factor protein Q01543 UNIPROT KLF1 factor protein Q13351 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets SIGNOR-256044 0.379 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT ZFPM1 factor protein Q8IX07 UNIPROT up-regulates activity binding 9606 21853041 t miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256059 0.792 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15767686 f irozzo These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1. SIGNOR-256070 0.2 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl NAB2 factor protein Q15742 UNIPROT GFI1 factor protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256042 0.407 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT FLI1 factor protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 f irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. SIGNOR-256053 0.538 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CBFB protein Q13951 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0002883 11179217 t The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis. SIGNOR-255742 0.838 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl FLI1 factor protein Q01543 UNIPROT GATA1 factor protein P15976 UNIPROT up-regulates activity binding 10090 BTO:0000944 12556498 t irozzo On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity. SIGNOR-256045 0.538 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 factor protein Q99684 UNIPROT SPI1 factor protein P17947 UNIPROT down-regulates activity binding 10090 BTO:0000725 17197705 t miannu Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. SIGNOR-256043 0.618 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CEBPA factor protein P49715 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17671233 f irozzo C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification. SIGNOR-256055 0.549 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT GATA1 factor protein P15976 UNIPROT down-regulates activity binding 10090 10364157 t irozzo We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation. SIGNOR-256049 0.647 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT TAL1 factor protein P17542 UNIPROT down-regulates activity binding 9606 BTO:0000567 16298389 t irozzo PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity SIGNOR-256048 0.458 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GFI1 factor protein Q99684 UNIPROT Granulocyte_differentiation phenotypesList phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 20861919 f irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256084 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 factor protein P11161 UNIPROT NAB2 factor protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 f miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. SIGNOR-253885 0.6 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 factor protein P23769 UNIPROT SPI1 factor protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000664 10411939 t irozzo Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes. SIGNOR-256071 0.602 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT NAB2 factor protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256039 0.314 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT JUN factor protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17041602 f miannu Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. SIGNOR-256065 0.577 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 f miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. SIGNOR-254190 0.489 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0002884 22012064 t irozzo Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression. SIGNOR-255874 0.413 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KLF1 factor protein Q13351 UNIPROT Erythrocyte_differentiation phenotypesList phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 f irozzo Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation. SIGNOR-256086 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl NAB2 factor protein Q15742 UNIPROT EGR2 factor protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253888 0.6 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl JUN factor protein P05412 UNIPROT Monocyte_differentiation phenotypesList phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 f miannu These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs. SIGNOR-256066 0.7 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA2 factor protein P23769 UNIPROT GATA2 factor protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27545880 f irozzo GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation SIGNOR-256090 0.2 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl ZFPM1 factor protein Q8IX07 UNIPROT GATA2 factor protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21853041 t miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. SIGNOR-256061 0.736 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl SPI1 factor protein P17947 UNIPROT EGR2 factor protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 f miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation SIGNOR-256040 0.384 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT GATA1 factor protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 f irozzo Furthermore, GATA-1 has been shown to auto-regulate its own gene expression. SIGNOR-256057 0.2 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl CEBPA factor protein P49715 UNIPROT CEBPA factor protein P49715 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001056 11283671 t apalma Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells. SIGNOR-255673 0.2 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl HRAS protein P01112 UNIPROT GATA2 factor protein P23769 UNIPROT up-regulates activity phosphorylation Ser192 PSTTGAAsPASSSAG 9606 25056917 f Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity SIGNOR-259945 0.367 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT SPI1 factor protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0004826 10753833 t irozzo GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region. SIGNOR-256050 0.647 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl JUN factor protein P05412 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-255660 0.577 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl GATA1 factor protein P15976 UNIPROT GATA2 factor protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12432220 f irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. SIGNOR-256058 0.415 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 22012064 t irozzo Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels SIGNOR-255707 0.544 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl EGR2 factor protein P11161 UNIPROT NAB2 factor protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 f miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. SIGNOR-253883 0.6 SIGNOR-AML_TF HaematopoiesisTranscriptionalControl KMT2A protein Q03164 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 23817177 t irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255708 0.544 SIGNOR-AML_TRIPLETS AML_TRIPLETS NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-AML_TRIPLETS AML_TRIPLETS FLT3 receptor protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.545 SIGNOR-AML_TRIPLETS AML_TRIPLETS AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-AML_TRIPLETS AML_TRIPLETS MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-AML_TRIPLETS AML_TRIPLETS NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-AML_TRIPLETS AML_TRIPLETS FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-AML_TRIPLETS AML_TRIPLETS NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-AML_TRIPLETS AML_TRIPLETS HOXA9 factor protein P31269 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.647 SIGNOR-AML_TRIPLETS AML_TRIPLETS FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243545 0.754 SIGNOR-AML_TRIPLETS AML_TRIPLETS DNMT3A protein Q9Y6K1 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255808 0.483 SIGNOR-AML_TRIPLETS AML_TRIPLETS FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-AML_TRIPLETS AML_TRIPLETS ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 factor protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 SIGNOR-AML_TRIPLETS AML_TRIPLETS GSK3B protein P49841 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc SIGNOR-118844 0.709 SIGNOR-AML_TRIPLETS AML_TRIPLETS DNMT3A protein Q9Y6K1 UNIPROT MEIS1 factor protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 f miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. SIGNOR-256125 0.338 SIGNOR-AML_TRIPLETS AML_TRIPLETS FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 30552988 f miannu Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. SIGNOR-260132 0.298 SIGNOR-AML_TRIPLETS AML_TRIPLETS CEBPA factor protein P49715 UNIPROT SOX4 factor protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.396 SIGNOR-AML_TRIPLETS AML_TRIPLETS MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-AML_TRIPLETS AML_TRIPLETS CEBPA factor protein P49715 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS GSK3B protein P49841 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. SIGNOR-144818 0.775 SIGNOR-AML_TRIPLETS AML_TRIPLETS ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-AML_TRIPLETS AML_TRIPLETS MEIS1 factor protein O00470 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-AML_TRIPLETS AML_TRIPLETS CCND1 factor protein P24385 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. SIGNOR-260014 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255754 0.661 SIGNOR-AML_TRIPLETS AML_TRIPLETS STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS NPM1 protein P06748 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.363 SIGNOR-AML_TRIPLETS AML_TRIPLETS FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.448 SIGNOR-AML_TRIPLETS AML_TRIPLETS STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-AML_TRIPLETS AML_TRIPLETS BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-AML_TRIPLETS AML_TRIPLETS TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS SOX4 factor protein Q06945 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. SIGNOR-260133 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS ETV6 factor protein P41212 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-AML_TRIPLETS AML_TRIPLETS MEIS1 factor protein O00470 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 SIGNOR-AML_TRIPLETS AML_TRIPLETS TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-AMPK AMPK Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 SIGNOR-AMPK AMPK Signaling IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-168985 0.708 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 SIGNOR-AMPK AMPK Signaling Starvation extracellular stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 23000343 f lperfetto Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV SIGNOR-209796 0.7 SIGNOR-AMPK AMPK Signaling ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMPK complex SIGNOR-C15 SIGNOR down-regulates activity phosphorylation 9606 21460634 t lperfetto Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. SIGNOR-209916 0.403 SIGNOR-AMPK AMPK Signaling PFKFB2 protein O60825 UNIPROT Glycolysis phenotypesList phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209950 0.7 SIGNOR-AMPK AMPK Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-AMPK AMPK Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.911 SIGNOR-AMPK AMPK Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 t lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 SIGNOR-209913 0.403 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.911 SIGNOR-AMPK AMPK Signaling mTORC1 complex SIGNOR-C3 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity SIGNOR-209904 0.561 SIGNOR-AMPK AMPK Signaling STRADA protein Q7RTN6 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity binding 9606 12805220 t Gianni Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 SIGNOR-247560 0.937 SIGNOR-AMPK AMPK Signaling RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-232208 0.791 SIGNOR-AMPK AMPK Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-AMPK AMPK Signaling TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250557 0.2 SIGNOR-AMPK AMPK Signaling Starvation extracellular stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0001760 20810907 f lperfetto L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells. SIGNOR-209894 0.7 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-244595 0.2 SIGNOR-AMPK AMPK Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-AMPK AMPK Signaling SIRT1 protein Q96EB6 UNIPROT PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity deacetylation 10090 BTO:0001103 24003218 t lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation SIGNOR-217963 0.792 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.911 SIGNOR-AMPK AMPK Signaling STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation -1 14976552 t lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). SIGNOR-242602 0.591 SIGNOR-AMPK AMPK Signaling RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. SIGNOR-209871 0.295 SIGNOR-AMPK AMPK Signaling ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro SIGNOR-209910 0.561 SIGNOR-AMPK AMPK Signaling mTORC1 complex SIGNOR-C3 SIGNOR Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR down-regulates 9606 23863160 f lperfetto Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer. SIGNOR-209922 0.7 SIGNOR-AMPK AMPK Signaling RPS6KA1 protein Q15418 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-217553 0.476 SIGNOR-AMPK AMPK Signaling SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. SIGNOR-252456 0.626 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249682 0.395 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation 9606 17900900 t lperfetto We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites SIGNOR-216481 0.395 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.911 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR up-regulates activity phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 t lperfetto GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation SIGNOR-217749 0.459 SIGNOR-AMPK AMPK Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.911 SIGNOR-AMPK AMPK Signaling RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000011 19299511 t lperfetto These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. SIGNOR-235355 0.791 SIGNOR-AMPK AMPK Signaling Starvation extracellular stimulus SIGNOR-ST4 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates activity 9606 BTO:0000759 15744310 f AMPK pathway Gianni We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. SIGNOR-261951 0.7 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.911 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249678 0.395 SIGNOR-AMPK AMPK Signaling PPARGC1A factor protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis SIGNOR-209932 0.7 SIGNOR-AMPK AMPK Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR INSR receptor protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 22207502 t lperfetto Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. SIGNOR-216619 0.31 SIGNOR-AMPK AMPK Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-AMPK AMPK Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249668 0.395 SIGNOR-AMPK AMPK Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.911 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209936 0.48 SIGNOR-AMPK AMPK Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.932 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-238813 0.395 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 20640476 t lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209947 0.388 SIGNOR-AMPK AMPK Signaling RPS6KA1 protein Q15418 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-217900 0.712 SIGNOR-AMPK AMPK Signaling RPS6KA1 protein Q15418 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-72117 0.738 SIGNOR-AMPK AMPK Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-AMPK AMPK Signaling FOXO3 factor protein O43524 UNIPROT Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR up-regulates activity 9606 BTO:0000007 22931788 f AMPK signaling Gianni Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. SIGNOR-261952 0.7 SIGNOR-AMPK AMPK Signaling mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249688 0.395 SIGNOR-AMPK AMPK Signaling SIRT1 protein Q96EB6 UNIPROT PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates quantity transcriptional regulation 9606 19553684 f gcesareni Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action SIGNOR-238790 0.792 SIGNOR-AMPK AMPK Signaling AMPK complex SIGNOR-C15 SIGNOR FOXO3 factor protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249685 0.395 SIGNOR-AMPK AMPK Signaling CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.911 SIGNOR-AMPK AMPK Signaling STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217469 0.591 SIGNOR-AMPK AMPK Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-AMPK AMPK Signaling SIRT1 protein Q96EB6 UNIPROT PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity deacetylation 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209962 0.792 SIGNOR-AMPK AMPK Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.911 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 SIGNOR-AMPK AMPK Signaling ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209907 0.7 SIGNOR-AMPK AMPK Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250558 0.2 SIGNOR-AMPK AMPK Signaling STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 14976552 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217472 0.591 SIGNOR-Autophagy Autophagy ATG4B protein Q9Y4P1 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity cleavage 9606 BTO:0000007;BTO:0000567 15187094 t lperfetto Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. SIGNOR-125489 0.748 SIGNOR-Autophagy Autophagy PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260320 0.892 SIGNOR-Autophagy Autophagy BECN1 protein Q14457 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260319 0.904 SIGNOR-Autophagy Autophagy AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000459 20921139 t lperfetto we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. SIGNOR-168252 0.78 SIGNOR-Autophagy Autophagy AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 17589504 t lperfetto Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy SIGNOR-156409 0.78 SIGNOR-Autophagy Autophagy Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260326 0.7 SIGNOR-Autophagy Autophagy ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209907 0.7 SIGNOR-Autophagy Autophagy ATG12 protein O94817 UNIPROT Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates 4932 23321721 f lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation SIGNOR-219396 0.7 SIGNOR-Autophagy Autophagy ATG7 protein O95352 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity binding 10090 22170151 t lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191540 0.779 SIGNOR-Autophagy Autophagy GABARAPL1 receptor protein Q9H0R8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 t lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha SIGNOR-156304 0.788 SIGNOR-Autophagy Autophagy ATG3 protein Q9NT62 UNIPROT GABARAP receptor protein O95166 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141868 0.841 SIGNOR-Autophagy Autophagy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 20083114 t lperfetto A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863. SIGNOR-216422 0.445 SIGNOR-Autophagy Autophagy SQSTM1 protein Q13501 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 19765191 t P00441:p.Ala5Val (mutation causing interaction)  This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway. SIGNOR-262801 0.532 SIGNOR-Autophagy Autophagy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 21460634 t miannu AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. SIGNOR-216418 0.445 SIGNOR-Autophagy Autophagy SOD1 protein P00441 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0001279 15233914 t P00441:p.Gly94Ala (mutation disrupting interaction) Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein. SIGNOR-262799 0.483 SIGNOR-Autophagy Autophagy UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000567 17106237 t lperfetto UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis. SIGNOR-150825 0.857 SIGNOR-Autophagy Autophagy UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 21311563 t lperfetto Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes SIGNOR-171902 0.857 SIGNOR-Autophagy Autophagy MAP1LC3C protein Q9BXW4 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates activity binding 10090 BTO:0002572 22170151 t lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191552 0.772 SIGNOR-Autophagy Autophagy GABARAP receptor protein O95166 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 11146101 t lperfetto N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions SIGNOR-219391 0.338 SIGNOR-Autophagy Autophagy ATG14 protein Q6ZNE5 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260318 0.908 SIGNOR-Autophagy Autophagy ATG4B protein Q9Y4P1 UNIPROT GABARAPL2 receptor protein P60520 UNIPROT up-regulates activity cleavage -1 16303767 t lperfetto In mammals, at least three atg8 homologs, lc3, gabarap, and gate-16, have been identified (fig. 1a), all of which have structural ubiquitin folds (1416). In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly SIGNOR-141932 0.838 SIGNOR-Autophagy Autophagy ATG4B protein Q9Y4P1 UNIPROT GABARAP receptor protein O95166 UNIPROT up-regulates activity cleavage -1 16303767 t lperfetto In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly SIGNOR-141929 0.856 SIGNOR-Autophagy Autophagy BECN1 protein Q14457 UNIPROT Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f miannu Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1–VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes. SIGNOR-219545 0.7 SIGNOR-Autophagy Autophagy ATG14 protein Q6ZNE5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 BTO:0000944 19270693 t lperfetto Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy, SIGNOR-235448 0.878 SIGNOR-Autophagy Autophagy Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260323 0.7 SIGNOR-Autophagy Autophagy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition SIGNOR-209862 0.445 SIGNOR-Autophagy Autophagy BECN1 protein Q14457 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260315 0.935 SIGNOR-Autophagy Autophagy Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260324 0.7 SIGNOR-Autophagy Autophagy MAP1LC3C protein Q9BXW4 UNIPROT Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219399 0.7 SIGNOR-Autophagy Autophagy ATG12/5/16L1 complex SIGNOR-C109 SIGNOR Autophagosome_formation phenotypesList phenotype SIGNOR-PH36 SIGNOR up-regulates -1 23321721 f lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation SIGNOR-226702 0.7 SIGNOR-Autophagy Autophagy ATG10 protein Q9H0Y0 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 t gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-180129 0.875 SIGNOR-Autophagy Autophagy ATG3 protein Q9NT62 UNIPROT GABARAPL2 receptor protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141926 0.869 SIGNOR-Autophagy Autophagy ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 t lperfetto Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-226699 0.778 SIGNOR-Autophagy Autophagy Starvation extracellular stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 23000343 f lperfetto Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV SIGNOR-209796 0.7 SIGNOR-Autophagy Autophagy Starvation extracellular stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0001760 20810907 f lperfetto L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells. SIGNOR-209894 0.7 SIGNOR-Autophagy Autophagy ATG7 protein O95352 UNIPROT GABARAPL2 receptor protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme). SIGNOR-142002 0.903 SIGNOR-Autophagy Autophagy GABARAPL2 receptor protein P60520 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 t lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha SIGNOR-156307 0.862 SIGNOR-Autophagy Autophagy mTORC1 complex SIGNOR-C3 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity SIGNOR-209904 0.561 SIGNOR-Autophagy Autophagy Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagy phenotypesList phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260325 0.7 SIGNOR-Autophagy Autophagy AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 t lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 SIGNOR-209913 0.403 SIGNOR-Autophagy Autophagy AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 18439900 t lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-216430 0.445 SIGNOR-Autophagy Autophagy PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 10090 19270693 t lperfetto The beclin 1-vps34 interaction regulates autophagy. SIGNOR-184521 0.934 SIGNOR-Autophagy Autophagy UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 9606 18843052 t lperfetto Although both human atg14 and uvrag interact with beclin 1 and vps34. SIGNOR-181554 0.804 SIGNOR-Autophagy Autophagy ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation 10090 20921139 t lperfetto When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation. SIGNOR-219388 0.655 SIGNOR-Autophagy Autophagy GFs extracellular stimulus SIGNOR-ST12 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates 9606 23863153 f lperfetto Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. SIGNOR-219382 0.7 SIGNOR-Autophagy Autophagy PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260316 0.917 SIGNOR-Autophagy Autophagy UVRAG protein Q9P2Y5 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260322 0.816 SIGNOR-Autophagy Autophagy BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 t gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. SIGNOR-154477 0.728 SIGNOR-B-cell B-cell activation SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr72 SDDFDSDyENPDEHS 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96044 0.8 SIGNOR-B-cell B-cell activation INPP5D protein Q92835 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268456 0.429 SIGNOR-B-cell B-cell activation BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268442 0.702 SIGNOR-B-cell B-cell activation AP1 factor complex SIGNOR-C154 SIGNOR NFATC1 factor protein O95644 UNIPROT up-regulates activity binding 9606 BTO:0000782 15928679 t Activator protein 1 (AP1) proteins are the main transcriptional partners of NFAT during T-cell activation SIGNOR-253004 0.649 SIGNOR-B-cell B-cell activation NFATC2 factor protein Q13469 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 f scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. SIGNOR-270538 0.7 SIGNOR-B-cell B-cell activation NFATC1 factor protein O95644 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 f scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. SIGNOR-270537 0.7 SIGNOR-B-cell B-cell activation CD19 receptor protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000899 10201980 t lperfetto Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. SIGNOR-252669 0.497 SIGNOR-B-cell B-cell activation PLCG2 protein P16885 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268453 0.8 SIGNOR-B-cell B-cell activation CD79A protein P11912 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268192 0.637 SIGNOR-B-cell B-cell activation CD22 protein P20273 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268444 0.2 SIGNOR-B-cell B-cell activation 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 SIGNOR-B-cell B-cell activation BLK protein P51451 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268217 0.63 SIGNOR-B-cell B-cell activation SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268458 0.2 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268215 0.696 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT CD19 receptor protein P15391 UNIPROT up-regulates activity phosphorylation Tyr500 TSLGSQSyEDMRGIL 10090 BTO:0000776 10933394 t lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni SIGNOR-249376 0.765 SIGNOR-B-cell B-cell activation BLK protein P51451 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268208 0.63 SIGNOR-B-cell B-cell activation SH2B1 protein Q9NRF2 UNIPROT CD79A protein P11912 UNIPROT down-regulates activity dephosphorylation 9606 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268457 0.2 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249339 0.551 SIGNOR-B-cell B-cell activation Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 factor protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252323 0.817 SIGNOR-B-cell B-cell activation LAT receptor protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.801 SIGNOR-B-cell B-cell activation PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-B-cell B-cell activation PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-B-cell B-cell activation SYK protein P43405 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 11226282 t lperfetto We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. SIGNOR-247586 0.567 SIGNOR-B-cell B-cell activation 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity precursor of 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268450 0.8 SIGNOR-B-cell B-cell activation BCR-Mk complex SIGNOR-C433 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268439 0.702 SIGNOR-B-cell B-cell activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 0.7 SIGNOR-B-cell B-cell activation INPP5D protein Q92835 UNIPROT PLCG2 protein P16885 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268455 0.319 SIGNOR-B-cell B-cell activation STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268209 0.696 SIGNOR-B-cell B-cell activation BLK protein P51451 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268211 0.63 SIGNOR-B-cell B-cell activation PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126066 0.387 SIGNOR-B-cell B-cell activation PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268207 0.616 SIGNOR-B-cell B-cell activation CD79B protein P40259 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268197 0.637 SIGNOR-B-cell B-cell activation 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity precursor of 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268451 0.8 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268216 0.616 SIGNOR-B-cell B-cell activation CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-252337 0.568 SIGNOR-B-cell B-cell activation CD79B protein P40259 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268189 0.637 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268213 0.616 SIGNOR-B-cell B-cell activation PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity 9606 BTO:0000938 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-252725 0.708 SIGNOR-B-cell B-cell activation antigen smallmolecule CHEBI:59132 ChEBI BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268204 0.8 SIGNOR-B-cell B-cell activation PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23140367 t miannu Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-251558 0.8 SIGNOR-B-cell B-cell activation Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 factor protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252319 0.633 SIGNOR-B-cell B-cell activation CD79A protein P11912 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268196 0.637 SIGNOR-B-cell B-cell activation BCR-Ml complex SIGNOR-C434 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268440 0.702 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268212 0.696 SIGNOR-B-cell B-cell activation PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-B-cell B-cell activation SH2B1 protein Q9NRF2 UNIPROT BLNK protein Q8WV28 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268446 0.2 SIGNOR-B-cell B-cell activation IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-B-cell B-cell activation antigen smallmolecule CHEBI:59132 ChEBI BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268202 0.8 SIGNOR-B-cell B-cell activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-B-cell B-cell activation SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr178 LLEDEADyVVPVEDN 9606 BTO:0000776 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96040 0.8 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT CD22 protein P20273 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino LYN is a BCR-associated SRC kinase involved in the positive regulation of BCR, but it also functions as a negative regulator by phosphorylating the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CD22. SIGNOR-268443 0.734 SIGNOR-B-cell B-cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 t miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. SIGNOR-255462 0.8 SIGNOR-B-cell B-cell activation AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-B-cell B-cell activation DOK3 protein Q7L591 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268448 0.576 SIGNOR-B-cell B-cell activation BLK protein P51451 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268214 0.63 SIGNOR-B-cell B-cell activation BCR-Dk complex SIGNOR-C435 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268441 0.702 SIGNOR-B-cell B-cell activation PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-B-cell B-cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249383 0.599 SIGNOR-B-cell B-cell activation 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i. SIGNOR-179291 0.8 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT DOK3 protein Q7L591 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268447 0.42 SIGNOR-B-cell B-cell activation PLCG2 protein P16885 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268454 0.8 SIGNOR-B-cell B-cell activation CD79B protein P40259 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268193 0.637 SIGNOR-B-cell B-cell activation CD79A protein P11912 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268188 0.637 SIGNOR-B-cell B-cell activation antigen smallmolecule CHEBI:59132 ChEBI BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268205 0.8 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268210 0.616 SIGNOR-B-cell B-cell activation GRB2 protein P62993 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268449 0.559 SIGNOR-B-cell B-cell activation PLCG2 protein P16885 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268452 0.8 SIGNOR-B-cell B-cell activation PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199. SIGNOR-99310 0.535 SIGNOR-B-cell B-cell activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-B-cell B-cell activation MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268206 0.696 SIGNOR-B-cell B-cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 t lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 0.8 SIGNOR-B-cell B-cell activation SH2B1 protein Q9NRF2 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 t scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. SIGNOR-268445 0.2 SIGNOR-B-cell B-cell activation CD79B protein P40259 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268201 0.637 SIGNOR-B-cell B-cell activation LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249381 0.639 SIGNOR-B-cell B-cell activation INPP5D protein Q92835 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 12421919 t gcesareni Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten SIGNOR-252428 0.8 SIGNOR-B-cell B-cell activation FYN protein P06241 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-148931 0.737 SIGNOR-B-cell B-cell activation BTK protein Q06187 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 11413148 t llicata Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity. SIGNOR-250603 0.482 SIGNOR-B-cell B-cell activation antigen smallmolecule CHEBI:59132 ChEBI BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268203 0.8 SIGNOR-B-cell B-cell activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon_Production phenotypesList phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-216322 0.7 SIGNOR-B-cell B-cell activation CD79A protein P11912 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268200 0.637 SIGNOR-CAC Citric acid cycle OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266258 0.8 SIGNOR-CAC Citric acid cycle FH protein P07954 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity chemical modification 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266280 0.8 SIGNOR-CAC Citric acid cycle ACO2 protein Q99798 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266246 0.8 SIGNOR-CAC Citric acid cycle acetyl-CoA smallmolecule CHEBI:15351 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266236 0.8 SIGNOR-CAC Citric acid cycle 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity precursor of 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266253 0.8 SIGNOR-CAC Citric acid cycle PDH complex SIGNOR-C402 SIGNOR acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266541 0.8 SIGNOR-CAC Citric acid cycle succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266265 0.8 SIGNOR-CAC Citric acid cycle citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267100 0.8 SIGNOR-CAC Citric acid cycle ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267102 0.8 SIGNOR-CAC Citric acid cycle pyruvate smallmolecule CHEBI:15361 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266542 0.8 SIGNOR-CAC Citric acid cycle Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266269 0.8 SIGNOR-CAC Citric acid cycle ACLY protein P53396 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267103 0.8 SIGNOR-CAC Citric acid cycle ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266245 0.8 SIGNOR-CAC Citric acid cycle p38 proteinfamily SIGNOR-PF16 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Thr90 GVTERMPtPVIKAFG 9606 BTO:0002058 30683654 t miannu In this study, we found that TGFβ induces FH Thr 90 phosphorylation by p38. Upon Notch activation, nuclear NICD promotes the interaction between CSL and p38-phosphorylated FH and thus FH/CSL/p53/Smad complex formation; this facilitates FH recruitment to p53-targed p21 promoter, where FH inhibits KDM2A-mediated demethylation of H3K36me2 through local production of fumarate SIGNOR-266316 0.2 SIGNOR-CAC Citric acid cycle Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266270 0.8 SIGNOR-CAC Citric acid cycle succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266266 0.8 SIGNOR-CAC Citric acid cycle SDH complex SIGNOR-C400 SIGNOR fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266277 0.8 SIGNOR-CAC Citric acid cycle fumarate(2-) smallmolecule CHEBI:29806 ChEBI (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity precursor of 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266278 0.8 SIGNOR-CAC Citric acid cycle oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266237 0.8 SIGNOR-CAC Citric acid cycle IDH complex SIGNOR-C396 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266252 0.8 SIGNOR-CAC Citric acid cycle MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266286 0.8 SIGNOR-CAC Citric acid cycle D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266250 0.8 SIGNOR-CAC Citric acid cycle citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266241 0.8 SIGNOR-CAC Citric acid cycle succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266275 0.8 SIGNOR-CAC Citric acid cycle acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotypesList phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 f Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo SIGNOR-267383 0.7 SIGNOR-CAC Citric acid cycle (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266282 0.8 SIGNOR-CAC Citric acid cycle MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266285 0.8 SIGNOR-CAC Citric acid cycle citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266243 0.8 SIGNOR-CAC Citric acid cycle CS protein O75390 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266240 0.8 SIGNOR-CAC Citric acid cycle AMPK complex SIGNOR-C15 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Ser75 YGAQTVRsTMNFKIG -1 28628081 t miannu Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes. SIGNOR-266313 0.2 SIGNOR-CB Carnitine biosynthesis 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269701 0.8 SIGNOR-CB Carnitine biosynthesis BBOX1 protein O75936 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269700 0.8 SIGNOR-CB Carnitine biosynthesis 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269686 0.8 SIGNOR-CB Carnitine biosynthesis SHMT1 protein P34896 UNIPROT glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269689 0.8 SIGNOR-CB Carnitine biosynthesis N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269685 0.8 SIGNOR-CB Carnitine biosynthesis BBOX1 protein O75936 UNIPROT carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269699 0.8 SIGNOR-CB Carnitine biosynthesis 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269691 0.8 SIGNOR-CB Carnitine biosynthesis TMLHE protein Q9NVH6 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269683 0.8 SIGNOR-CB Carnitine biosynthesis 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269690 0.8 SIGNOR-CB Carnitine biosynthesis SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SIGNOR-269688 0.8 SIGNOR-CB Carnitine biosynthesis TMLHE protein Q9NVH6 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity chemical modification 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269684 0.8 SIGNOR-CB Carnitine biosynthesis ALDH9A1 protein P49189 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269693 0.8 SIGNOR-CB Carnitine biosynthesis 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity precursor of 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269696 0.8 SIGNOR-CC Circadian clock ARNTL receptor protein O00327 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 t lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. SIGNOR-253708 0.764 SIGNOR-CC Circadian clock SIRT1 protein Q96EB6 UNIPROT PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21633182 t miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. SIGNOR-268033 0.792 SIGNOR-CC Circadian clock SCF-betaTRCP complex SIGNOR-C5 SIGNOR PER2 protein O15055 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17876059 t miannu Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity. SIGNOR-268055 0.461 SIGNOR-CC Circadian clock BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267967 0.891 SIGNOR-CC Circadian clock NPAS2 protein Q99743 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267966 0.512 SIGNOR-CC Circadian clock CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 15767683 t miannu The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. SIGNOR-267995 0.897 SIGNOR-CC Circadian clock NR1D2 factor protein Q14995 UNIPROT ARNTL receptor protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268006 0.488 SIGNOR-CC Circadian clock CRY2 protein Q49AN0 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267972 0.892 SIGNOR-CC Circadian clock FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotypesList phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 f miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site SIGNOR-268159 0.7 SIGNOR-CC Circadian clock NR3C1 factor protein P04150 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268050 0.274 SIGNOR-CC Circadian clock BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267968 0.892 SIGNOR-CC Circadian clock RORA receptor protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267980 0.652 SIGNOR-CC Circadian clock BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267969 0.736 SIGNOR-CC Circadian clock PPARG factor protein P37231 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19041764 t miannu  Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms. SIGNOR-268026 0.411 SIGNOR-CC Circadian clock AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser280 YKKVKKNsSPPLSLY 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268047 0.346 SIGNOR-CC Circadian clock PPARG factor protein P37231 UNIPROT NR1D1 factor protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12821652 t miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. SIGNOR-268022 0.282 SIGNOR-CC Circadian clock NR1D1 factor protein P20393 UNIPROT ARNTL receptor protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20817722 t miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267983 0.661 SIGNOR-CC Circadian clock NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12555668 t gcesareni Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi SIGNOR-238602 0.8 SIGNOR-CC Circadian clock NR3C1 factor protein P04150 UNIPROT NFIL3 factor protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268051 0.303 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253680 0.927 SIGNOR-CC Circadian clock glucocorticoid smallmolecule CHEBI:24261 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates activity binding 9606 18049904 t miannu Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. SIGNOR-268048 0.8 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253682 0.748 SIGNOR-CC Circadian clock NR1D1 factor protein P20393 UNIPROT NPAS2 protein Q99743 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20817722 t miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267981 0.618 SIGNOR-CC Circadian clock CRY1 protein Q16526 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267975 0.937 SIGNOR-CC Circadian clock SIRT1 protein Q96EB6 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 19299583 t lperfetto Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression. SIGNOR-253722 0.772 SIGNOR-CC Circadian clock NFIL3 factor protein Q16649 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11316793 t miannu E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence SIGNOR-268056 0.357 SIGNOR-CC Circadian clock SIRT6 protein Q8N6T7 UNIPROT SREBF1 factor protein P36956 UNIPROT up-regulates activity binding 9606 BTO:0000007 25083875 t miannu SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids. SIGNOR-268158 0.384 SIGNOR-CC Circadian clock AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216647 0.48 SIGNOR-CC Circadian clock CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267999 0.796 SIGNOR-CC Circadian clock SIRT1 protein Q96EB6 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21633182 t miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. SIGNOR-268032 0.689 SIGNOR-CC Circadian clock PPARGC1A factor protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis SIGNOR-209932 0.7 SIGNOR-CC Circadian clock CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268000 0.863 SIGNOR-CC Circadian clock TIMELESS protein Q9UNS1 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates activity binding 9534 23418588 t miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. SIGNOR-268053 0.701 SIGNOR-CC Circadian clock CLOCK factor protein O15516 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 t lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. SIGNOR-253709 0.764 SIGNOR-CC Circadian clock CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268001 0.796 SIGNOR-CC Circadian clock RORB protein Q92753 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268003 0.498 SIGNOR-CC Circadian clock CRY2 protein Q49AN0 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267976 0.927 SIGNOR-CC Circadian clock BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267970 0.7 SIGNOR-CC Circadian clock PPARA factor protein Q07869 UNIPROT Fatty_acid_oxidation phenotypesList phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001103;BTO:0000671 18836859 f miannu PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart SIGNOR-268027 0.7 SIGNOR-CC Circadian clock NR3C1 factor protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268052 0.256 SIGNOR-CC Circadian clock PPARGC1A factor protein Q9UBK2 UNIPROT NR1D1 factor protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 17476214 t miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state. SIGNOR-268030 0.5 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253679 0.937 SIGNOR-CC Circadian clock CSNK1D protein P48730 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267998 0.711 SIGNOR-CC Circadian clock PPARGC1A factor protein Q9UBK2 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17476214 t miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. SIGNOR-268031 0.497 SIGNOR-CC Circadian clock NR1D1 factor protein P20393 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 12821652 f miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. SIGNOR-268023 0.7 SIGNOR-CC Circadian clock CRY1 protein Q16526 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267971 0.891 SIGNOR-CC Circadian clock AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268046 0.346 SIGNOR-CC Circadian clock SREBF1 factor protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-142294 0.518 SIGNOR-CC Circadian clock SREBF1 factor protein P36956 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates activity 10090 9539737 f gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 0.468 SIGNOR-CC Circadian clock SIRT6 protein Q8N6T7 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates activity binding 9606 BTO:0000007 25083875 t miannu SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1. SIGNOR-268157 0.381 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253683 0.588 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253681 0.716 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19299583 t miannu Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E). SIGNOR-268021 0.598 SIGNOR-CC Circadian clock NR3C1 factor protein P04150 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 t miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription SIGNOR-268049 0.476 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR DBP protein Q10586 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 30100984 t miannu The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). SIGNOR-268029 0.699 SIGNOR-CC Circadian clock SERPINE1 extracellular protein P05121 UNIPROT Fibrinolysis extracellular phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 19387897 f miannu Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms. SIGNOR-267984 0.7 SIGNOR-CC Circadian clock NR1D1 factor protein P20393 UNIPROT ARNTL receptor protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268005 0.661 SIGNOR-CC Circadian clock PER2 protein O15055 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267973 0.736 SIGNOR-CC Circadian clock DBP protein Q10586 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 21633182 f miannu In addition to NHRs, Dbp, a known clock target gene, regulates expression of key metabolic genes involved in gluconeogenesis and lipogenesis (60). Because DBP levels change 100-fold in response to CLOCK/BMAL1 activation, it is conceivable that DBP generates circadian oscillation in metabolic processes such as gluconeogenesis. SIGNOR-268028 0.7 SIGNOR-CC Circadian clock RORA receptor protein P35398 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268002 0.678 SIGNOR-CC Circadian clock RORA receptor protein P35398 UNIPROT NR1D1 factor protein P20393 UNIPROT down-regulates activity binding 9606 BTO:0000599 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267979 0.434 SIGNOR-CC Circadian clock CLOCK factor protein O15516 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 t lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription SIGNOR-253711 0.665 SIGNOR-CC Circadian clock PER1 protein O15534 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267978 0.716 SIGNOR-CC Circadian clock PPARA factor protein Q07869 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16556735 t miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. SIGNOR-268024 0.576 SIGNOR-CC Circadian clock PER1 protein O15534 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267974 0.7 SIGNOR-CC Circadian clock AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216651 0.48 SIGNOR-CC Circadian clock CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253713 0.495 SIGNOR-CC Circadian clock ARNTL receptor protein O00327 UNIPROT PPARA factor protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 16556735 t miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. SIGNOR-268025 0.576 SIGNOR-CC Circadian clock RORA receptor protein P35398 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267982 0.678 SIGNOR-CC Circadian clock CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267997 0.833 SIGNOR-CC Circadian clock CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267996 0.734 SIGNOR-CC Circadian clock CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253712 0.504 SIGNOR-CC Circadian clock PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267977 0.748 SIGNOR-CC Circadian clock CLOCK factor protein O15516 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267965 0.512 SIGNOR-CC Circadian clock NAD(1-) smallmolecule CHEBI:57540 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 10693811 t gcesareni Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases SIGNOR-238539 0.8 SIGNOR-CC Circadian clock RORC factor protein P51449 UNIPROT ARNTL receptor protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 t miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. SIGNOR-268004 0.522 SIGNOR-CC Circadian clock RAI1 protein Q7Z5J4 UNIPROT CLOCK factor protein O15516 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 t miannu RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266839 0.453 SIGNOR-CCN COVID-19 Causal Network Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260865 0.7 SIGNOR-CCN COVID-19 Causal Network CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.787 SIGNOR-CCN COVID-19 Causal Network aloxistatin extracellular chemical CHEBI:101381 ChEBI CTSB protein P07858 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260281 0.8 SIGNOR-CCN COVID-19 Causal Network ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260158 0.493 SIGNOR-CCN COVID-19 Causal Network IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-CCN COVID-19 Causal Network M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0005029 25271362 f Luana Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein. SIGNOR-260200 0.2 SIGNOR-CCN COVID-19 Causal Network Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256375 0.797 SIGNOR-CCN COVID-19 Causal Network SACM1L protein Q9NTJ5 UNIPROT phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI down-regulates quantity chemical modification 9534 22253445 t lperfetto To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P. SIGNOR-260733 0.8 SIGNOR-CCN COVID-19 Causal Network KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 12228228 t gcesareni Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module. SIGNOR-92793 0.376 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9534 15294014 f Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. SIGNOR-261131 0.2 SIGNOR-CCN COVID-19 Causal Network PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 SIGNOR-CCN COVID-19 Causal Network BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 SIGNOR-CCN COVID-19 Causal Network TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-CCN COVID-19 Causal Network MAVS protein Q7Z434 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260152 0.2 SIGNOR-CCN COVID-19 Causal Network MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260144 0.823 SIGNOR-CCN COVID-19 Causal Network Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 SIGNOR-CCN COVID-19 Causal Network EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR) SIGNOR-260168 0.715 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0001950 21561061 t Luana Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260759 0.736 SIGNOR-CCN COVID-19 Causal Network CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.787 SIGNOR-CCN COVID-19 Causal Network Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT MAS1 receptor protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 SIGNOR-CCN COVID-19 Causal Network CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260743 0.7 SIGNOR-CCN COVID-19 Causal Network RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.733 SIGNOR-CCN COVID-19 Causal Network CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. SIGNOR-260741 0.7 SIGNOR-CCN COVID-19 Causal Network CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260744 0.7 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260446 0.7 SIGNOR-CCN COVID-19 Causal Network SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 t miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression SIGNOR-260437 0.593 SIGNOR-CCN COVID-19 Causal Network RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 24726876 t miannu RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260945 0.2 SIGNOR-CCN COVID-19 Causal Network ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates activity 9606 31226023 f miannu The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK) SIGNOR-260177 0.325 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 f Luana We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner SIGNOR-260219 0.7 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 f Luana In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SIGNOR-260204 0.7 SIGNOR-CCN COVID-19 Causal Network Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260245 0.2 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 f Luana SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway SIGNOR-260205 0.7 SIGNOR-CCN COVID-19 Causal Network ATF4 factor protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260172 0.651 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. SIGNOR-260199 0.7 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 16965829 f Luana Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells SIGNOR-260194 0.7 SIGNOR-CCN COVID-19 Causal Network 6 protein P59634 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 f Luana A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis SIGNOR-260203 0.7 SIGNOR-CCN COVID-19 Causal Network 7a protein P59635 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260209 0.7 SIGNOR-CCN COVID-19 Causal Network 7b protein Q7TFA1 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260210 0.7 SIGNOR-CCN COVID-19 Causal Network AGTR2 receptor protein P50052 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 32201502 f MIANNU AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth SIGNOR-260232 0.7 SIGNOR-CCN COVID-19 Causal Network BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.789 SIGNOR-CCN COVID-19 Causal Network AGTR1 receptor protein P30556 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 SIGNOR-CCN COVID-19 Causal Network CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites. SIGNOR-98280 0.347 SIGNOR-CCN COVID-19 Causal Network Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 f miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260163 0.7 SIGNOR-CCN COVID-19 Causal Network ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-CCN COVID-19 Causal Network Camostat extracellular chemical CID:2536 ChEBI TMPRSS2 receptor protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 32142651 t miannu Indeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells (Figure 4 A). Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260284 0.8 SIGNOR-CCN COVID-19 Causal Network EP300 factor protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 t miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. SIGNOR-260431 0.726 SIGNOR-CCN COVID-19 Causal Network ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t Luana Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-260755 0.2 SIGNOR-CCN COVID-19 Causal Network TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-CCN COVID-19 Causal Network CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.617 SIGNOR-CCN COVID-19 Causal Network Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT up-regulates activity binding 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260226 0.2 SIGNOR-CCN COVID-19 Causal Network AP-2/clathrin vescicle receptor complex SIGNOR-C249 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260704 0.7 SIGNOR-CCN COVID-19 Causal Network FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260629 0.503 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.818 SIGNOR-CCN COVID-19 Causal Network BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1. SIGNOR-56399 0.836 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 21561061 f Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260760 0.2 SIGNOR-CCN COVID-19 Causal Network AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. SIGNOR-251473 0.2 SIGNOR-CCN COVID-19 Causal Network SMAD7 protein O15105 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 30017632 t miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). SIGNOR-260438 0.781 SIGNOR-CCN COVID-19 Causal Network EIF2S1 protein P05198 UNIPROT ATF4 factor protein P18848 UNIPROT down-regulates quantity transcriptional regulation 9606 27629041 t miannu ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery SIGNOR-260169 0.628 SIGNOR-CCN COVID-19 Causal Network MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260145 0.91 SIGNOR-CCN COVID-19 Causal Network BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-CCN COVID-19 Causal Network LARP4B protein Q92615 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 20573744 f miannu Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs. SIGNOR-260942 0.7 SIGNOR-CCN COVID-19 Causal Network E protein P59637 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 10090 BTO:0000763 25122212 f Luana Interestingly, an increase in p38 MAPK activation was observed during infection with viruses containing E protein PBM, similarly to what was observed in the lungs of SARS-CoV-infected mice. These results indicated that the E protein PBM is involved in p38 MAPK activation in response to SARS-CoV infection. SIGNOR-260751 0.2 SIGNOR-CCN COVID-19 Causal Network FAS receptor protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.906 SIGNOR-CCN COVID-19 Causal Network TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-CCN COVID-19 Causal Network p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-260443 0.2 SIGNOR-CCN COVID-19 Causal Network aloxistatin extracellular chemical CHEBI:101381 ChEBI CTSL protein P07711 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260282 0.8 SIGNOR-CCN COVID-19 Causal Network ATF2 factor protein P15336 UNIPROT IL6 extracellular protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254512 0.306 SIGNOR-CCN COVID-19 Causal Network Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260866 0.7 SIGNOR-CCN COVID-19 Causal Network LARP4B protein Q92615 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260940 0.571 SIGNOR-CCN COVID-19 Causal Network Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR2 receptor protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 SIGNOR-CCN COVID-19 Causal Network PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT up-regulates activity binding 9606 30209168 t miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling SIGNOR-260968 0.799 SIGNOR-CCN COVID-19 Causal Network MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.721 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-CCN COVID-19 Causal Network Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 24168260 f miannu We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis. SIGNOR-260447 0.2 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0000298 15294014 f Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. SIGNOR-261132 0.2 SIGNOR-CCN COVID-19 Causal Network MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-CCN COVID-19 Causal Network Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 SIGNOR-CCN COVID-19 Causal Network Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 f miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260190 0.7 SIGNOR-CCN COVID-19 Causal Network CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.59 SIGNOR-CCN COVID-19 Causal Network CCL2 extracellular protein P13500 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 f Luana In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. SIGNOR-261317 0.7 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.576 SIGNOR-CCN COVID-19 Causal Network 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0001950 18632968 f Luana Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation SIGNOR-260193 0.2 SIGNOR-CCN COVID-19 Causal Network EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-CCN COVID-19 Causal Network ATF6 protein P18850 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260184 0.683 SIGNOR-CCN COVID-19 Causal Network Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260142 0.7 SIGNOR-CCN COVID-19 Causal Network CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-CCN COVID-19 Causal Network p38 proteinfamily SIGNOR-PF16 SIGNOR DDIT3 factor protein P35638 UNIPROT up-regulates activity phosphorylation -1 8650547 t Luana Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase SIGNOR-260724 0.2 SIGNOR-CCN COVID-19 Causal Network MAS1 receptor protein P04201 UNIPROT AGTR1 receptor protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 t miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex SIGNOR-260626 0.282 SIGNOR-CCN COVID-19 Causal Network CASP8 protein Q14790 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-90612 0.7 SIGNOR-CCN COVID-19 Causal Network STING1 protein Q86WV6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260153 0.2 SIGNOR-CCN COVID-19 Causal Network AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-CCN COVID-19 Causal Network RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT up-regulates activity binding 9606 BTO:0005238 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260941 0.2 SIGNOR-CCN COVID-19 Causal Network TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-CCN COVID-19 Causal Network DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260139 0.935 SIGNOR-CCN COVID-19 Causal Network IFNAR receptor complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 SIGNOR-CCN COVID-19 Causal Network 4E2RCat chemical CID:2287236 ChEBI EIF4E protein P06730 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 t miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. SIGNOR-260187 0.8 SIGNOR-CCN COVID-19 Causal Network MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 SIGNOR-59679 0.427 SIGNOR-CCN COVID-19 Causal Network 7a protein P59635 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000007 16378980 f Luana While there is a low level of activated p38 normally found in 293T cells, expression of 7a-protein stimulated larger amounts of activated p38 during the 24-h time course.  SIGNOR-260754 0.2 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.362 SIGNOR-CCN COVID-19 Causal Network JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 0.2 SIGNOR-CCN COVID-19 Causal Network TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.838 SIGNOR-CCN COVID-19 Causal Network REN extracellular protein P00797 UNIPROT Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260225 0.2 SIGNOR-CCN COVID-19 Causal Network ATF6 protein P18850 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260180 0.647 SIGNOR-CCN COVID-19 Causal Network TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-CCN COVID-19 Causal Network CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.617 SIGNOR-CCN COVID-19 Causal Network TGFBR1 receptor protein P36897 UNIPROT SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 f miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. SIGNOR-260590 0.45 SIGNOR-CCN COVID-19 Causal Network Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 f miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260175 0.7 SIGNOR-CCN COVID-19 Causal Network AP1 factor complex SIGNOR-C154 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 t Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity SIGNOR-260764 0.602 SIGNOR-CCN COVID-19 Causal Network CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-CCN COVID-19 Causal Network DDIT3 factor protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260173 0.474 SIGNOR-CCN COVID-19 Causal Network TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-CCN COVID-19 Causal Network 8a protein Q7TFA0 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 f Luana Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis SIGNOR-260206 0.7 SIGNOR-CCN COVID-19 Causal Network Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR1 receptor protein P30556 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260238 0.2 SIGNOR-CCN COVID-19 Causal Network ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-CCN COVID-19 Causal Network 9b protein P59636 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260241 0.2 SIGNOR-CCN COVID-19 Causal Network MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w SIGNOR-151787 0.718 SIGNOR-CCN COVID-19 Causal Network EIF2AK3 protein Q9NZJ5 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates phosphorylation Tyr619 NKVDDCNyAIKRIRL 9606 17998206 t lperfetto We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity. SIGNOR-159156 0.2 SIGNOR-CCN COVID-19 Causal Network MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 t miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity SIGNOR-260160 0.92 SIGNOR-CCN COVID-19 Causal Network Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260141 0.7 SIGNOR-CCN COVID-19 Causal Network BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-131442 0.817 SIGNOR-CCN COVID-19 Causal Network SERPINE1 extracellular protein P05121 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 f miannu Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. SIGNOR-260588 0.7 SIGNOR-CCN COVID-19 Causal Network BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000093 22464442 t lperfetto Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer. SIGNOR-209675 0.85 SIGNOR-CCN COVID-19 Causal Network TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-260151 0.2 SIGNOR-CCN COVID-19 Causal Network NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256381 0.2 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-CCN COVID-19 Causal Network BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.838 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-CCN COVID-19 Causal Network AGT extracellular protein P01019 UNIPROT REN extracellular protein P00797 UNIPROT up-regulates activity binding 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260224 0.927 SIGNOR-CCN COVID-19 Causal Network PPP2CA protein P67775 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 24726876 t miannu RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260944 0.318 SIGNOR-CCN COVID-19 Causal Network Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3 SIGNOR-260246 0.2 SIGNOR-CCN COVID-19 Causal Network IL6 extracellular protein P05231 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260256 0.7 SIGNOR-CCN COVID-19 Causal Network ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-CCN COVID-19 Causal Network DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260192 0.271 SIGNOR-CCN COVID-19 Causal Network M protein P59596 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity 9606 25271362 f Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  SIGNOR-260201 0.2 SIGNOR-CCN COVID-19 Causal Network TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-CCN COVID-19 Causal Network 3a protein P59632 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR down-regulates quantity 9606 20020050 f miannu The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity. SIGNOR-260350 0.2 SIGNOR-CCN COVID-19 Causal Network 8b protein Q80H93 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. SIGNOR-260240 0.2 SIGNOR-CCN COVID-19 Causal Network 8a protein Q7TFA0 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. SIGNOR-260239 0.2 SIGNOR-CCN COVID-19 Causal Network 6 protein P59634 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260339 0.2 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260338 0.2 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260337 0.2 SIGNOR-CCN COVID-19 Causal Network G3BP2 protein Q9UN86 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 10969074 t SARA IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm. SIGNOR-260985 0.348 SIGNOR-CCN COVID-19 Causal Network TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-CCN COVID-19 Causal Network ORF4b protein K9N643 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity binding 9606 26631542 t miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm SIGNOR-260592 0.2 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-CCN COVID-19 Causal Network MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.682 SIGNOR-CCN COVID-19 Causal Network CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR AP-2/clathrin vescicle receptor complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260756 0.2 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P0DTC2 UNIPROT CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 t miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. SIGNOR-260739 0.2 SIGNOR-CCN COVID-19 Causal Network E protein P59637 UNIPROT SDCBP extracellular protein O00560 UNIPROT up-regulates activity relocalization 9534 25122212 t Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. SIGNOR-260752 0.2 SIGNOR-CCN COVID-19 Causal Network HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT down-regulates activity binding 9606 31226023 t miannu Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78 SIGNOR-260179 0.817 SIGNOR-CCN COVID-19 Causal Network 9b protein P59636 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260242 0.2 SIGNOR-CCN COVID-19 Causal Network ACE2 receptor protein Q9BYF1 UNIPROT CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 t miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. SIGNOR-260740 0.2 SIGNOR-CCN COVID-19 Causal Network E protein P59637 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity 9606 BTO:0000661 16048439 f Luana SARS-CoV E protein induces apoptosis by ‘sequestering’ Bcl-xL to the membranes of ER and Golgi, where the SARS-CoV E protein is located. As a consequence, the existing balance between pro-survival protein Bcl-xL and pro-apoptotic proteins, including Bax and BH3-domain-only proteins, is tipped by SARS CoV E protein, so that sequestered Bcl-xL could not fulfil its normal function in inhibition of apoptosis. | This result implied that SARS-CoV E protein might induce T-cell apoptosis via a pathway antagonistic to the mitochondrion-dependent mechanism of Bcl-xL. SIGNOR-260586 0.2 SIGNOR-CCN COVID-19 Causal Network PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity dephosphorylation 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-254119 0.425 SIGNOR-CCN COVID-19 Causal Network TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 SIGNOR-CCN COVID-19 Causal Network TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-CCN COVID-19 Causal Network TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260156 0.9 SIGNOR-CCN COVID-19 Causal Network MAPK8 protein P45983 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant SIGNOR-183489 0.555 SIGNOR-CCN COVID-19 Causal Network 3a protein P59632 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 18632968 f Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. SIGNOR-260214 0.2 SIGNOR-CCN COVID-19 Causal Network BCL2L11 protein O43521 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 18055455 t miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. SIGNOR-260434 0.2 SIGNOR-CCN COVID-19 Causal Network Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE receptor protein P12821 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260231 0.2 SIGNOR-CCN COVID-19 Causal Network TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-CCN COVID-19 Causal Network CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp403 LPAADMDdFSRQLQN 9534 BTO:0001444 18155731 t Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 SIGNOR-260212 0.2 SIGNOR-CCN COVID-19 Causal Network CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp400 VTLLPAAdMDDFSRQ 9534 BTO:0001444 18155731 t Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 SIGNOR-260211 0.2 SIGNOR-CCN COVID-19 Causal Network JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo. SIGNOR-261133 0.2 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260329 0.2 SIGNOR-CCN COVID-19 Causal Network phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. SIGNOR-260745 0.7 SIGNOR-CCN COVID-19 Causal Network 3a protein P59632 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 18632968 f Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. SIGNOR-260213 0.2 SIGNOR-CCN COVID-19 Causal Network M protein P59596 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 25271362 f Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  SIGNOR-260202 0.2 SIGNOR-CCN COVID-19 Causal Network JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 f miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. SIGNOR-260178 0.7 SIGNOR-CCN COVID-19 Causal Network CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-CCN COVID-19 Causal Network PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka. SIGNOR-126659 0.2 SIGNOR-CCN COVID-19 Causal Network JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260149 0.716 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity 9606 21561061 f Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260761 0.2 SIGNOR-CCN COVID-19 Causal Network NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. SIGNOR-260346 0.7 SIGNOR-CCN COVID-19 Causal Network LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 20573744 f miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. SIGNOR-260939 0.7 SIGNOR-CCN COVID-19 Causal Network ER stress extracellular stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196941 0.7 SIGNOR-CCN COVID-19 Causal Network AKT proteinfamily SIGNOR-PF24 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates -1 14663477 f Luana Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt. SIGNOR-260215 0.7 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 14623261 t Luana Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway. SIGNOR-260725 0.2 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260445 0.7 SIGNOR-CCN COVID-19 Causal Network KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.84 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 f miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. SIGNOR-260353 0.2 SIGNOR-CCN COVID-19 Causal Network FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260628 0.264 SIGNOR-CCN COVID-19 Causal Network TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-CCN COVID-19 Causal Network AGTR1 receptor protein P30556 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260234 0.7 SIGNOR-CCN COVID-19 Causal Network AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-172132 0.418 SIGNOR-CCN COVID-19 Causal Network TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-CCN COVID-19 Causal Network DDIT3 factor protein P35638 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236110 0.736 SIGNOR-CCN COVID-19 Causal Network ACE receptor protein P12821 UNIPROT Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260236 0.2 SIGNOR-CCN COVID-19 Causal Network MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-CCN COVID-19 Causal Network AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 f Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer SIGNOR-260766 0.7 SIGNOR-CCN COVID-19 Causal Network FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 SIGNOR-CCN COVID-19 Causal Network EIF2AK2 protein P19525 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260159 0.7 SIGNOR-CCN COVID-19 Causal Network chloroquine extracellular chemical CHEBI:3638 ChEBI ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 t miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells SIGNOR-260223 0.8 SIGNOR-CCN COVID-19 Causal Network IFNAR receptor complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260146 0.8 SIGNOR-CCN COVID-19 Causal Network MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260723 0.71 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 t Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well SIGNOR-260729 0.2 SIGNOR-CCN COVID-19 Causal Network APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . SIGNOR-135381 0.953 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 t Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well SIGNOR-260727 0.2 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 t lperfetto Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-83729 0.736 SIGNOR-CCN COVID-19 Causal Network BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-CCN COVID-19 Causal Network SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-CCN COVID-19 Causal Network ACE2 receptor protein Q9BYF1 UNIPROT Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 SIGNOR-CCN COVID-19 Causal Network CTSB protein P07858 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 t miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260738 0.2 SIGNOR-CCN COVID-19 Causal Network TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260148 0.721 SIGNOR-CCN COVID-19 Causal Network CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.787 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 f miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. SIGNOR-260351 0.2 SIGNOR-CCN COVID-19 Causal Network CTSL protein P07711 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 t miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260737 0.2 SIGNOR-CCN COVID-19 Causal Network TMPRSS2 receptor protein O15393 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32142651 t miannu Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells SIGNOR-260736 0.2 SIGNOR-CCN COVID-19 Causal Network CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. SIGNOR-53585 0.876 SIGNOR-CCN COVID-19 Causal Network HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 9606 31226023 t miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260176 0.815 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-CCN COVID-19 Causal Network Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260867 0.7 SIGNOR-CCN COVID-19 Causal Network MAS1 receptor protein P04201 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 SIGNOR-CCN COVID-19 Causal Network FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18055455 f miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. SIGNOR-260589 0.2 SIGNOR-CCN COVID-19 Causal Network Caspase 1 complex complex SIGNOR-C220 SIGNOR IL18 extracellular protein Q14116 UNIPROT up-regulates activity cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 t lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256377 0.785 SIGNOR-CCN COVID-19 Causal Network BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 BTO:0000007 11997495 t lperfetto We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome. SIGNOR-87280 0.823 SIGNOR-CCN COVID-19 Causal Network IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-CCN COVID-19 Causal Network JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 0.2 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21561061 f Luana 3b Augments c-Fos Levels by Activating the ERK Pathway. | An increase of∼2.0-fold inphospho ERK (Thr-202/Tyr-204) levels in 3b-expressing Huh7cells as compared to GFP-transfected control cells (Figure 4a)was observed. This increase in phospho ERK levels was also SIGNOR-260763 0.2 SIGNOR-CCN COVID-19 Causal Network SMAD3 protein P84022 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 SIGNOR-CCN COVID-19 Causal Network MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 10480932 t Luana P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-260720 0.728 SIGNOR-CCN COVID-19 Causal Network CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-CCN COVID-19 Causal Network Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 SIGNOR-CCN COVID-19 Causal Network Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFITMs receptor proteinfamily SIGNOR-PF49 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 25599080 f miannu The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons SIGNOR-260220 0.2 SIGNOR-CCN COVID-19 Causal Network XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 f miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. SIGNOR-260186 0.7 SIGNOR-CCN COVID-19 Causal Network EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-CCN COVID-19 Causal Network FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 SIGNOR-CCN COVID-19 Causal Network EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-CCN COVID-19 Causal Network NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-CCN COVID-19 Causal Network RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-CCN COVID-19 Causal Network DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260191 0.33 SIGNOR-CCN COVID-19 Causal Network E protein P59637 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity 9534 BTO:0001444 22028656 f miannu SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. SIGNOR-260347 0.2 SIGNOR-CCN COVID-19 Causal Network Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity binding 9606 22312431 t miannu Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING SIGNOR-260247 0.2 SIGNOR-CCN COVID-19 Causal Network Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256376 0.797 SIGNOR-CCN COVID-19 Causal Network EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 11381086 f miannu Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis.  SIGNOR-260625 0.7 SIGNOR-CCN COVID-19 Causal Network ATF2 factor protein P15336 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 f Luana ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. SIGNOR-261324 0.7 SIGNOR-CCN COVID-19 Causal Network EIF4E protein P06730 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 SIGNOR-CCN COVID-19 Causal Network G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 t miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. SIGNOR-260750 0.315 SIGNOR-CCN COVID-19 Causal Network SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260425 0.475 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. SIGNOR-255693 0.7 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR TNF extracellular protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 0.666 SIGNOR-CCN COVID-19 Causal Network MAVS protein Q7Z434 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 t miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  SIGNOR-260143 0.794 SIGNOR-CCN COVID-19 Causal Network CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-126727 0.515 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-CCN COVID-19 Causal Network ATF4 factor protein P18848 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260170 0.81 SIGNOR-CCN COVID-19 Causal Network TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-CCN COVID-19 Causal Network MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-CCN COVID-19 Causal Network MAS1 receptor protein P04201 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 9606 26460884 t miannu We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases SIGNOR-260627 0.2 SIGNOR-CCN COVID-19 Causal Network CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.787 SIGNOR-CCN COVID-19 Causal Network ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-CCN COVID-19 Causal Network PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-CCN COVID-19 Causal Network TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-CCN COVID-19 Causal Network N protein P0DTC9 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity binding 9606 32353859 t miannu N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms SIGNOR-260749 SIGNOR-CCN COVID-19 Causal Network MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51199 0.682 SIGNOR-CCN COVID-19 Causal Network SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-CCN COVID-19 Causal Network CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 t miannu We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization SIGNOR-260748 0.242 SIGNOR-CCN COVID-19 Causal Network G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260864 0.7 SIGNOR-CCN COVID-19 Causal Network CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-CCN COVID-19 Causal Network TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 t gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 0.44 SIGNOR-CCN COVID-19 Causal Network HSPA5 protein P11021 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 31226023 t miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260164 0.715 SIGNOR-CCN COVID-19 Causal Network BCL2L1 protein Q07817 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 9670005 t amattioni The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal. SIGNOR-59141 0.727 SIGNOR-CCN COVID-19 Causal Network G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection SIGNOR-260747 0.7 SIGNOR-CCN COVID-19 Causal Network IFNAR receptor complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 SIGNOR-CCN COVID-19 Causal Network IKBKE protein Q14164 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260155 0.622 SIGNOR-CCN COVID-19 Causal Network PI4KB protein Q9UBF8 UNIPROT phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI up-regulates quantity chemical modification 9534 22253445 t lperfetto Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry. SIGNOR-260732 0.8 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260722 0.57 SIGNOR-CCN COVID-19 Causal Network MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-CCN COVID-19 Causal Network JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.812 SIGNOR-CCN COVID-19 Causal Network Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260587 0.7 SIGNOR-CCN COVID-19 Causal Network CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity 9606 16940539 f miannu SARS-CoV S protein specifically activated PERK but did not significantly affect IRE1/XBP1 or ATF6. SIGNOR-260439 0.2 SIGNOR-CCN COVID-19 Causal Network IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-CCN COVID-19 Causal Network Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist SIGNOR-260248 0.2 SIGNOR-CCN COVID-19 Causal Network MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR down-regulates quantity binding 9606 BTO:0000763 18055455 t miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. SIGNOR-260427 0.2 SIGNOR-CCN COVID-19 Causal Network GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-CCN COVID-19 Causal Network IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260140 0.809 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 t lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction SIGNOR-178053 0.622 SIGNOR-CCN COVID-19 Causal Network AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-CCN COVID-19 Causal Network EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation. SIGNOR-260165 0.756 SIGNOR-CCN COVID-19 Causal Network SDCBP extracellular protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0001444 25122212 f Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. SIGNOR-260753 0.2 SIGNOR-CCN COVID-19 Causal Network CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-59857 0.716 SIGNOR-CCN COVID-19 Causal Network PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-CCN COVID-19 Causal Network N protein P59595 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein. SIGNOR-260340 0.2 SIGNOR-CCN COVID-19 Causal Network MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 9430721 t Luana The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms SIGNOR-260721 0.728 SIGNOR-CCN COVID-19 Causal Network 9b protein P59636 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260243 0.2 SIGNOR-CCN COVID-19 Causal Network EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 31226023 f miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes. SIGNOR-260166 0.7 SIGNOR-CCN COVID-19 Causal Network TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-CCN COVID-19 Causal Network 3b protein P59633 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 21561061 f Luana SARS-CoV Accessory Protein 3b Induces AP-1 TranscriptionalActivity SIGNOR-260757 0.2 SIGNOR-CCN COVID-19 Causal Network TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-CCN COVID-19 Causal Network ORF4b protein K9N643 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 26631542 t miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm SIGNOR-260593 0.2 SIGNOR-CCN COVID-19 Causal Network ERN1 protein O75460 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 31226023 t miannu Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity. SIGNOR-260183 0.64 SIGNOR-CCN COVID-19 Causal Network G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260863 0.468 SIGNOR-CCN COVID-19 Causal Network AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-CCN COVID-19 Causal Network PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-260174 0.685 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 16988814 t miannu In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of ANG II from ANG I is enhanced by ACE, and ANG II induces acute lung failure through stimulation of the AT1 receptor, while ACE2 and ANG II type 2 receptor negatively regulate this pathway and protect from acute lung failure. On the other hand, SARS-CoV infection is mediated through binding of the SARS-Spike protein to ACE2 or L-SIGN and down-regulates the protective molecule ACE2, and thus leads to severe lung injury and acute lung failure SIGNOR-260291 0.2 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 14670965 t miannu The coronavirus spike (S) protein mediates infection of receptor-expressing host cells and is a critical target for antiviral neutralizing antibodies. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for the coronavirus (severe acute respiratory syndrome (SARS)-CoV) that causes SARS. Here we demonstrate that a 193-amino acid fragment of the S protein (residues 318-510) bound ACE2 more efficiently than did the full S1 domain (residues 12-672). Smaller S protein fragments, expressing residues 327-510 or 318-490, did not detectably bind ACE2. SIGNOR-260216 0.2 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9534 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260283 0.2 SIGNOR-CCN COVID-19 Causal Network S extracellular protein P0DTC2 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 32125455 t miannu SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. SIGNOR-260742 0.2 SIGNOR-CCN COVID-19 Causal Network ER stress extracellular stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196944 0.7 SIGNOR-CCN COVID-19 Causal Network NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255356 0.566 SIGNOR-CCN COVID-19 Causal Network G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260862 0.468 SIGNOR-CCN COVID-19 Causal Network Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260348 0.2 SIGNOR-CM Catecholamine metabolism MAOA protein P21397 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264003 0.8 SIGNOR-CM Catecholamine metabolism TPH1 protein P17752 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264010 0.8 SIGNOR-CM Catecholamine metabolism noradrenaline smallmolecule CHEBI:33569 ChEBI adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity precursor of 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264183 0.8 SIGNOR-CM Catecholamine metabolism DDC protein P20711 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-263994 0.8 SIGNOR-CM Catecholamine metabolism TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-263991 0.8 SIGNOR-CM Catecholamine metabolism L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264184 0.8 SIGNOR-CM Catecholamine metabolism PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity chemical modification 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264007 0.8 SIGNOR-CM Catecholamine metabolism 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264178 0.8 SIGNOR-CM Catecholamine metabolism tyrosine smallmolecule CHEBI:18186 ChEBI L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-264173 0.8 SIGNOR-CM Catecholamine metabolism DDC protein P20711 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity chemical modification 7955 23940784 t brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin SIGNOR-263987 0.8 SIGNOR-CM Catecholamine metabolism PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-263989 0.8 SIGNOR-CM Catecholamine metabolism L-dopa smallmolecule CHEBI:15765 ChEBI dopamine extracellular smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal SIGNOR-264174 0.8 SIGNOR-CM Catecholamine metabolism COMT protein P21964 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263998 0.8 SIGNOR-CM Catecholamine metabolism dopamine extracellular smallmolecule CHEBI:18243 ChEBI noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity precursor of 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264182 0.8 SIGNOR-CM Catecholamine metabolism DDC protein P20711 UNIPROT dopamine extracellular smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 7955 23940784 t brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin SIGNOR-263986 0.8 SIGNOR-CM Catecholamine metabolism serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264187 0.8 SIGNOR-CM Catecholamine metabolism dopamine extracellular smallmolecule CHEBI:18243 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264180 0.8 SIGNOR-CM Catecholamine metabolism 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT SIGNOR-264186 0.8 SIGNOR-CM Catecholamine metabolism tyrosine smallmolecule CHEBI:18186 ChEBI tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć SIGNOR-264175 0.8 SIGNOR-CM Catecholamine metabolism CYP2D6 protein P10635 UNIPROT dopamine extracellular smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-263996 0.8 SIGNOR-CM Catecholamine metabolism phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-264172 0.8 SIGNOR-CM Catecholamine metabolism DBH extracellular protein P09172 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity chemical modification 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264006 0.8 SIGNOR-CM Catecholamine metabolism tyramine smallmolecule CHEBI:15760 ChEBI dopamine extracellular smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† SIGNOR-264176 0.8 SIGNOR-CM Catecholamine metabolism dopamine extracellular smallmolecule CHEBI:18243 ChEBI 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264177 0.8 SIGNOR-CRC Colorectal Carcinoma TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.838 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 0.2 SIGNOR-CRC Colorectal Carcinoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 SIGNOR-CRC Colorectal Carcinoma TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-CRC Colorectal Carcinoma DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 0.2 SIGNOR-CRC Colorectal Carcinoma TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-CRC Colorectal Carcinoma BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 SIGNOR-CRC Colorectal Carcinoma IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251492 0.669 SIGNOR-CRC Colorectal Carcinoma LEF1 factor protein Q9UJU2 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.622 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 t lperfetto Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin SIGNOR-227862 0.891 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 SIGNOR-CRC Colorectal Carcinoma SMAD4 protein Q13485 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251493 0.627 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158636 0.839 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates phosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21199 0.2 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage. SIGNOR-126757 0.839 SIGNOR-CRC Colorectal Carcinoma IGF2 extracellular protein P01344 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251495 0.817 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 0.891 SIGNOR-CRC Colorectal Carcinoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251128 0.2 SIGNOR-CRC Colorectal Carcinoma MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 0.7 SIGNOR-CRC Colorectal Carcinoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-CRC Colorectal Carcinoma WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131574 0.78 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227889 0.891 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 t flangone Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway. SIGNOR-70477 0.795 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. SIGNOR-167152 0.839 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-CRC Colorectal Carcinoma WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169645 0.78 SIGNOR-CRC Colorectal Carcinoma PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-209856 0.724 SIGNOR-CRC Colorectal Carcinoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115348 0.839 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124860 0.2 SIGNOR-CRC Colorectal Carcinoma TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t giulio giuliani In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa) SIGNOR-255960 0.838 SIGNOR-CRC Colorectal Carcinoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-244877 0.611 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 SIGNOR-CRC Colorectal Carcinoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251130 0.2 SIGNOR-CRC Colorectal Carcinoma TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-CRC Colorectal Carcinoma BRAF protein P15056 UNIPROT TGFB1 extracellular protein P01137 UNIPROT up-regulates quantity relocalization 9606 19861538 f miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. SIGNOR-251987 0.252 SIGNOR-CRC Colorectal Carcinoma SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 f gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes SIGNOR-123087 0.671 SIGNOR-CRC Colorectal Carcinoma TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 0.838 SIGNOR-CRC Colorectal Carcinoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115344 0.839 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 t  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251127 0.2 SIGNOR-CRC Colorectal Carcinoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170465 0.2 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-CRC Colorectal Carcinoma DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 f miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 0.7 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 t llicata Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. SIGNOR-250576 0.2 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170473 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244862 0.743 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21211 0.2 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26586 0.2 SIGNOR-CRC Colorectal Carcinoma SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16766264 f irozzo This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. SIGNOR-256294 0.2 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.737 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 0.2 SIGNOR-CRC Colorectal Carcinoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-CRC Colorectal Carcinoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 SIGNOR-CRC Colorectal Carcinoma SMAD4 protein Q13485 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-229311 0.677 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 t gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. SIGNOR-21203 0.2 SIGNOR-CRC Colorectal Carcinoma LEF1 factor protein Q9UJU2 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229767 0.7 SIGNOR-CRC Colorectal Carcinoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115340 0.839 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-CRC Colorectal Carcinoma TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. SIGNOR-126753 0.839 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 0.2 SIGNOR-CRC Colorectal Carcinoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-CRC Colorectal Carcinoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-CRC Colorectal Carcinoma SMAD3 protein P84022 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-229308 0.534 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246252 0.2 SIGNOR-CRC Colorectal Carcinoma LRP5 receptor protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 t lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes SIGNOR-227930 0.672 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 t lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 0.891 SIGNOR-CRC Colorectal Carcinoma TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-CRC Colorectal Carcinoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227885 0.891 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244858 0.743 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-CRC Colorectal Carcinoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 t lperfetto Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-227866 0.891 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170477 0.2 SIGNOR-CRC Colorectal Carcinoma CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 SIGNOR-CRC Colorectal Carcinoma TGFBR1 receptor protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 f MARCO ROSINA TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad SIGNOR-255033 0.32 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 t Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251129 0.2 SIGNOR-CRC Colorectal Carcinoma SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.691 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 t lperfetto Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. SIGNOR-244739 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 0.891 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 SIGNOR-CRC Colorectal Carcinoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-CRC Colorectal Carcinoma KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 t gcesareni DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation SIGNOR-167156 0.839 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.891 SIGNOR-CRC Colorectal Carcinoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 t miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. SIGNOR-151138 0.839 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT ERBB2 receptor protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000150 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124856 0.2 SIGNOR-CRC Colorectal Carcinoma LEF1 factor protein Q9UJU2 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158632 0.839 SIGNOR-CRC Colorectal Carcinoma MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-CRC Colorectal Carcinoma ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 21149446 t gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. SIGNOR-170469 0.2 SIGNOR-CRC Colorectal Carcinoma ERBB2 receptor protein P04626 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 14967450 t gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor SIGNOR-121968 0.843 SIGNOR-CRC Colorectal Carcinoma GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 0.891 SIGNOR-CRC Colorectal Carcinoma SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251494 0.671 SIGNOR-CRC Colorectal Carcinoma TGFB1 extracellular protein P01137 UNIPROT TGFB1 extracellular protein P01137 UNIPROT up-regulates activity binding 9606 16885528 t lperfetto The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge. SIGNOR-148605 0.2 SIGNOR-CRC Colorectal Carcinoma KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.907 SIGNOR-CRC Colorectal Carcinoma TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.838 SIGNOR-CRC Colorectal Carcinoma PIK3CA protein P42336 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 SIGNOR-CRC Colorectal Carcinoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-CRC Colorectal Carcinoma TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 t miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 0.806 SIGNOR-CS Complement Signaling Complement C1 complex extracellular complex SIGNOR-C309 SIGNOR C4A extracellular protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263433 0.631 SIGNOR-CS Complement Signaling MASP2 extracellular protein O00187 UNIPROT C4A extracellular protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263431 0.792 SIGNOR-CS Complement Signaling C3AR1 receptor protein Q16581 UNIPROT Chemotaxis phenotypesList phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263471 0.7 SIGNOR-CS Complement Signaling MASP1 extracellular protein P48740 UNIPROT C2 extracellular protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263417 0.512 SIGNOR-CS Complement Signaling Membrane attack complex extracellular complex SIGNOR-C313 SIGNOR Cell_killing extracellular phenotype SIGNOR-PH149 SIGNOR up-regulates -1 30552328 f lperfetto Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions. SIGNOR-263454 0.7 SIGNOR-CS Complement Signaling C3 convertase complex extracellular complex SIGNOR-C310 SIGNOR C3 extracellular protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 31331124 t lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway SIGNOR-263449 0.537 SIGNOR-CS Complement Signaling Membrane attack complex extracellular complex SIGNOR-C313 SIGNOR Membrane_disruption extracellular phenotype SIGNOR-PH151 SIGNOR up-regulates -1 30552328 f lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers SIGNOR-263456 0.7 SIGNOR-CS Complement Signaling Immune complexes extracellular stimulus SIGNOR-ST15 SIGNOR Complement C1q extracellular complex SIGNOR-C308 SIGNOR up-regulates activity binding -1 29449492 t lperfetto We used IgG monoclonal antibodies (mAbs) oligomerized through antigen-binding on liposomes or preformed antibody complexes in solution and applied tomography and single-particle cryo–electron microscopy (cryo-EM) to resolve the mechanisms of C1 binding and activation.|Binding of C1 through its gC1q modules to mediators of inflammation, such as immunoglobulin G (IgG) or IgM antibodies (fig. S1, C and D), on cell surfaces activates the associated proteases and initiates the proteolytic cascade of complement SIGNOR-263397 0.7 SIGNOR-CS Complement Signaling MASP1 extracellular protein P48740 UNIPROT C4A extracellular protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263432 0.59 SIGNOR-CS Complement Signaling C5AR1 receptor protein P21730 UNIPROT Chemotaxis phenotypesList phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263460 0.7 SIGNOR-CS Complement Signaling Complement C1q extracellular complex SIGNOR-C308 SIGNOR Complement C1 complex extracellular complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 t lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases SIGNOR-263396 0.61 SIGNOR-CS Complement Signaling C5 extracellular protein P01031 UNIPROT C5AR1 receptor protein P21730 UNIPROT up-regulates activity binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 1847994 t complement C5a (anaphylatoxin) fragment: PRO_0000005988 lperfetto The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells. SIGNOR-263457 0.747 SIGNOR-CS Complement Signaling MBL2 extracellular protein P11226 UNIPROT MASP1 extracellular protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263414 0.742 SIGNOR-CS Complement Signaling C5AR1 receptor protein P21730 UNIPROT superoxide extracellular smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263469 0.8 SIGNOR-CS Complement Signaling MBL2 extracellular protein P11226 UNIPROT MASP2 extracellular protein O00187 UNIPROT up-regulates activity binding 9606 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263415 0.731 SIGNOR-CS Complement Signaling C3 convertase complex extracellular complex SIGNOR-C310 SIGNOR C5 convertase complex extracellular complex SIGNOR-C312 SIGNOR form complex binding 31331124 t lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. SIGNOR-263447 0.548 SIGNOR-CS Complement Signaling Complement C1 complex extracellular complex SIGNOR-C309 SIGNOR C2 extracellular protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 31331124 t lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex SIGNOR-263418 0.474 SIGNOR-CS Complement Signaling C3 extracellular protein P01024 UNIPROT C5 convertase complex extracellular complex SIGNOR-C312 SIGNOR form complex binding cleavage:Arg748 ASHLGLArSNLDEDI 31331124 t complement C3b fragment: PRO_0000005911 lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. SIGNOR-263448 0.2 SIGNOR-CS Complement Signaling MASP2 extracellular protein O00187 UNIPROT C2 extracellular protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase SIGNOR-263416 0.412 SIGNOR-CS Complement Signaling C2 extracellular protein P06681 UNIPROT C3 convertase complex extracellular complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg243 KTKESLGrKIQIQRS 17204478 t complement C2a fragment: PRO_0000027612 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263399 0.626 SIGNOR-CS Complement Signaling C4A extracellular protein P0C0L4 UNIPROT C3 convertase complex extracellular complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t complement C4b fragment: PRO_0000005970 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263400 0.603 SIGNOR-CS Complement Signaling C3AR1 receptor protein Q16581 UNIPROT Vascular_Permeability phenotypesList phenotype SIGNOR-PH140 SIGNOR up-regulates 10984054 f lperfetto The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability SIGNOR-263458 0.7 SIGNOR-CS Complement Signaling C5 extracellular protein P01031 UNIPROT Membrane attack complex extracellular complex SIGNOR-C313 SIGNOR form complex binding -1 cleavage:Arg751 HKDMQLGrLHMKTLL 30552328 t complement C5b fragment: PRO_0000005989 lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263440 0.604 SIGNOR-CS Complement Signaling C3 extracellular protein P01024 UNIPROT C3AR1 receptor protein Q16581 UNIPROT up-regulates activity binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 t complement C3a fragment: PRO_0000005910 lperfetto A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. SIGNOR-263451 0.722 SIGNOR-CS Complement Signaling C5 convertase complex extracellular complex SIGNOR-C312 SIGNOR C5 extracellular protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 31331124 t lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b SIGNOR-263452 0.533 SIGNOR-CS Complement Signaling C3AR1 receptor protein Q16581 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0001669 9108406 f lperfetto  In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes. SIGNOR-263472 0.7 SIGNOR-CS Complement Signaling PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR MBL2 extracellular protein P11226 UNIPROT up-regulates activity binding 17204478 t lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) SIGNOR-263405 0.7 SIGNOR-CS Complement Signaling C5AR1 receptor protein P21730 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263462 0.7 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Thr302 PEPEVLStQEDLFDQ 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197619 0.87 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100649 0.87 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72072 0.813 SIGNOR-DD DNA repair in cancer BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204538 0.529 SIGNOR-DD DNA repair in cancer ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259064 0.7 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187591 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner SIGNOR-81395 0.831 SIGNOR-DD DNA repair in cancer POLH protein Q9Y253 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21242293 f miannu In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control. SIGNOR-259061 0.7 SIGNOR-DD DNA repair in cancer CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner SIGNOR-133375 0.837 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR SLX4 protein Q8IY92 UNIPROT up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259063 0.7 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 f miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. SIGNOR-259062 0.7 SIGNOR-DD DNA repair in cancer RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 t fstefani To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-157478 0.2 SIGNOR-DD DNA repair in cancer RAD50 protein Q92878 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 10426999 t amattioni Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex. SIGNOR-69701 0.776 SIGNOR-DD DNA repair in cancer RAD51 protein Q06609 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells SIGNOR-251508 0.7 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr SIGNOR-87850 0.831 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72048 0.813 SIGNOR-DD DNA repair in cancer BRCA1 protein P38398 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-251500 0.7 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-72075 0.813 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106440 0.791 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 t lperfetto Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair SIGNOR-171290 0.427 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72068 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387. SIGNOR-81438 0.831 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100645 0.87 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. SIGNOR-242616 0.7 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250581 0.791 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 t llicata The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data SIGNOR-156077 0.805 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 t lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. SIGNOR-73366 0.2 SIGNOR-DD DNA repair in cancer SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 t lperfetto Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. SIGNOR-217652 0.812 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 9606 15342490 t miannu Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. SIGNOR-259059 0.473 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro. SIGNOR-81407 0.831 SIGNOR-DD DNA repair in cancer PALB2 protein Q86YC2 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0001938 19369211 t lperfetto The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. SIGNOR-244487 0.845 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72056 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo, SIGNOR-72079 0.813 SIGNOR-DD DNA repair in cancer TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 10090 23333305 t miannu RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination. SIGNOR-259058 0.669 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT up-regulates activity 9606 BTO:0001938 19369211 f lperfetto Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations. SIGNOR-244490 0.7 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-72052 0.813 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 SIGNOR-DD DNA repair in cancer PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage. SIGNOR-185656 0.745 SIGNOR-DD DNA repair in cancer BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198467 0.813 SIGNOR-DD DNA repair in cancer MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 29175432 f MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans SIGNOR-257600 0.7 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250582 0.791 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197615 0.87 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163106 0.841 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.831 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81391 0.831 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100653 0.87 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Thr1394 SQSDILTtQQRDTMQ 9606 BTO:0002181 11114888 t llicata Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250583 0.791 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81399 0.831 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106432 0.791 SIGNOR-DD DNA repair in cancer PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 t miannu Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. SIGNOR-147217 0.941 SIGNOR-DD DNA repair in cancer PALB2 protein Q86YC2 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204541 0.513 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72060 0.813 SIGNOR-DD DNA repair in cancer CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 t gcesareni In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites. SIGNOR-120575 0.78 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells. SIGNOR-201050 0.791 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106436 0.791 SIGNOR-DD DNA repair in cancer RIF1 protein Q5UIP0 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 15342490 f miannu This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred. SIGNOR-259060 0.7 SIGNOR-DD DNA repair in cancer ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment SIGNOR-150870 0.731 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-87845 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. SIGNOR-197611 0.87 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163110 0.841 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 t gcesareni Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-91482 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells. SIGNOR-197622 0.87 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72064 0.813 SIGNOR-DD DNA repair in cancer ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100641 0.87 SIGNOR-DD DNA repair in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11447297 t lperfetto Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect. SIGNOR-109243 0.938 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 t amattioni Xiap is an endogenous inhibitor of caspase-3 SIGNOR-110837 0.938 SIGNOR-DR Death Receptor Signaling APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . SIGNOR-135381 0.953 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 t amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). SIGNOR-71954 0.938 SIGNOR-DR Death Receptor Signaling TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.935 SIGNOR-DR Death Receptor Signaling RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 12887920 t amattioni Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex SIGNOR-104255 0.906 SIGNOR-DR Death Receptor Signaling FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-DR Death Receptor Signaling FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-173429 0.784 SIGNOR-DR Death Receptor Signaling CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.787 SIGNOR-DR Death Receptor Signaling DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9606 BTO:0000007;BTO:0000567 14523016 t amattioni Smac3, a novel Smac/DIABLO splicing variant, accelerates XIAP auto-ubiquitination and destruction SIGNOR-118411 0.912 SIGNOR-DR Death Receptor Signaling BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-DR Death Receptor Signaling CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-DR Death Receptor Signaling DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000567 11583623 t Smac/DIABLO released from mitochondria amattioni Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity SIGNOR-110831 0.912 SIGNOR-DR Death Receptor Signaling APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 t gcesareni During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation. SIGNOR-53579 0.953 SIGNOR-DR Death Receptor Signaling BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.615 SIGNOR-DR Death Receptor Signaling CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-DR Death Receptor Signaling CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.787 SIGNOR-DR Death Receptor Signaling CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination -1 15749826 t lperfetto Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis. SIGNOR-134504 0.912 SIGNOR-DR Death Receptor Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-DR Death Receptor Signaling CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-DR Death Receptor Signaling APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. SIGNOR-53576 0.953 SIGNOR-DR Death Receptor Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-DR Death Receptor Signaling TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-DR Death Receptor Signaling RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 21525013 t amattioni Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex SIGNOR-173432 0.906 SIGNOR-DR Death Receptor Signaling FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 SIGNOR-DR Death Receptor Signaling PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-DR Death Receptor Signaling TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-DR Death Receptor Signaling FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.784 SIGNOR-DR Death Receptor Signaling CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.617 SIGNOR-DR Death Receptor Signaling FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 SIGNOR-DR Death Receptor Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-DR Death Receptor Signaling BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 t amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. SIGNOR-73902 0.817 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 11242052 t lperfetto A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis SIGNOR-105702 0.92 SIGNOR-DR Death Receptor Signaling BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-DR Death Receptor Signaling BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 SIGNOR-DR Death Receptor Signaling CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.787 SIGNOR-DR Death Receptor Signaling CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.617 SIGNOR-DR Death Receptor Signaling BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-87109 0.524 SIGNOR-DR Death Receptor Signaling DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000567 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-80218 0.912 SIGNOR-DR Death Receptor Signaling CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.787 SIGNOR-DR Death Receptor Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-DR Death Receptor Signaling FAS receptor protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.906 SIGNOR-DR Death Receptor Signaling CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.59 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 t lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis SIGNOR-56484 0.92 SIGNOR-DR Death Receptor Signaling CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-DR Death Receptor Signaling XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding -1 12620238 t lperfetto This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity. SIGNOR-98988 0.92 SIGNOR-DR Death Receptor Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-DS Dopaminergic Synapse DRD5 receptor protein P21918 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257369 0.481 SIGNOR-DS Dopaminergic Synapse PKA proteinfamily SIGNOR-PF17 SIGNOR PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264956 0.2 SIGNOR-DS Dopaminergic Synapse CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 t llicata We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-250671 0.77 SIGNOR-DS Dopaminergic Synapse ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-DS Dopaminergic Synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 SIGNOR-DS Dopaminergic Synapse CREB1 factor protein P16220 UNIPROT BDNF extracellular protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 t miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. SIGNOR-265062 0.512 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD2 receptor protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258717 0.8 SIGNOR-DS Dopaminergic Synapse GNAL protein P38405 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates activity binding 9606 BTO:0004032 21303898 t miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. SIGNOR-264997 0.598 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD3 receptor protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258377 0.8 SIGNOR-DS Dopaminergic Synapse BDNF extracellular protein P23560 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain SIGNOR-265063 0.7 SIGNOR-DS Dopaminergic Synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity chemical activation 9606 24564659 t miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264692 0.8 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD4 receptor protein P21917 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257480 0.8 SIGNOR-DS Dopaminergic Synapse 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 receptor protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIGNOR-DS Dopaminergic Synapse GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-37149 0.76 SIGNOR-DS Dopaminergic Synapse DRD1 receptor protein P21728 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257335 0.474 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD5 receptor protein P21918 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257481 0.8 SIGNOR-DS Dopaminergic Synapse AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 f miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264695 0.7 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD3 receptor protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258716 0.8 SIGNOR-DS Dopaminergic Synapse PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD3 receptor protein P35462 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257479 0.8 SIGNOR-DS Dopaminergic Synapse GNB5 protein O14775 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264998 0.426 SIGNOR-DS Dopaminergic Synapse PPP1R1B protein Q9UD71 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 9606 BTO:0000938 10604473 t miannu We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-265087 0.478 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD2 receptor protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258376 0.8 SIGNOR-DS Dopaminergic Synapse PPP1CA protein P62136 UNIPROT AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR down-regulates activity dephosphorylation 9606 14751588 t miannu Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. Phosphorylation of AMPA receptors due to DARPP-32/PP1 signaling cascade increases AMPA channel activity and currents SIGNOR-265060 0.501 SIGNOR-DS Dopaminergic Synapse DRD4 receptor protein P21917 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264995 0.432 SIGNOR-DS Dopaminergic Synapse ADCY5 protein O95622 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-264999 0.8 SIGNOR-DS Dopaminergic Synapse NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264691 0.7 SIGNOR-DS Dopaminergic Synapse DRD3 receptor protein P35462 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264994 0.422 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD1 receptor protein P21728 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257477 0.8 SIGNOR-DS Dopaminergic Synapse dopamine extracellular smallmolecule CHEBI:18243 ChEBI DRD2 receptor protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257478 0.8 SIGNOR-DS Dopaminergic Synapse DRD1 receptor protein P21728 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256939 0.556 SIGNOR-DS Dopaminergic Synapse PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 SIGNOR-DS Dopaminergic Synapse DRD2 receptor protein P14416 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264993 0.581 SIGNOR-DS Dopaminergic Synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 SIGNOR-DS Dopaminergic Synapse 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-DS Dopaminergic Synapse PPP1R1B protein Q9UD71 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 t miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  SIGNOR-264957 0.578 SIGNOR-DS Dopaminergic Synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264696 0.8 SIGNOR-DS Dopaminergic Synapse PPP1CA protein P62136 UNIPROT NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0000142 14751588 t miannu DARPP-32/PP1 cascade modulates the physiological properties of NMDA and AMPA receptors, and activation of the DARPP-32/PP1 signaling leads to parallel increase in the phosphorylation of NMDA receptor subunits and intracellular Ca2+ levels SIGNOR-265061 0.2 SIGNOR-DS Dopaminergic Synapse DRD5 receptor protein P21918 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256914 0.489 SIGNOR-EGF EGFR Signaling SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44866 0.648 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236392 0.749 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 t lperfetto Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3, SIGNOR-235704 0.591 SIGNOR-EGF EGFR Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-EGF EGFR Signaling JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS factor protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251524 0.2 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites SIGNOR-235738 0.921 SIGNOR-EGF EGFR Signaling ERRFI1 protein Q9UJM3 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity binding -1 18046415 t The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 SIGNOR-252076 0.662 SIGNOR-EGF EGFR Signaling NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9534 8824201 t lperfetto We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-236324 0.695 SIGNOR-EGF EGFR Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto Akt phosphorylated sek1 on serine 78. SIGNOR-244285 0.2 SIGNOR-EGF EGFR Signaling STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236420 0.749 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma). SIGNOR-233233 0.749 SIGNOR-EGF EGFR Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-EGF EGFR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity binding 10090 BTO:0000944 1333047 t We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues SIGNOR-252089 0.594 SIGNOR-EGF EGFR Signaling SRC protein P12931 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 25157176 t Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis SIGNOR-252093 0.767 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 t Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, SIGNOR-248666 0.865 SIGNOR-EGF EGFR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-EGF EGFR Signaling ERRFI1 protein Q9UJM3 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001867 20421427 t We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes SIGNOR-252073 0.662 SIGNOR-EGF EGFR Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). SIGNOR-251419 0.736 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin SIGNOR-248670 0.635 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS factor protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251522 0.2 SIGNOR-EGF EGFR Signaling GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-83343 0.423 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-EGF EGFR Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-EGF EGFR Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-EGF EGFR Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236366 0.965 SIGNOR-EGF EGFR Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236254 0.951 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236408 0.749 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252086 0.2 SIGNOR-EGF EGFR Signaling EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates binding 9606 12648462 t lperfetto The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen SIGNOR-22716 0.949 SIGNOR-EGF EGFR Signaling MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 8131746 t lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. SIGNOR-244881 0.641 SIGNOR-EGF EGFR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-EGF EGFR Signaling HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 t gcesareni In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-35878 0.922 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 11350724 t lperfetto Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways. SIGNOR-107712 0.91 SIGNOR-EGF EGFR Signaling mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-EGF EGFR Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236396 0.749 SIGNOR-EGF EGFR Signaling NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0002572 10026169 t lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-236512 0.695 SIGNOR-EGF EGFR Signaling SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 9566874 t lperfetto Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. SIGNOR-235445 0.782 SIGNOR-EGF EGFR Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236412 0.749 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 t lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-236432 0.489 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248674 0.951 SIGNOR-EGF EGFR Signaling SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. SIGNOR-247341 0.782 SIGNOR-EGF EGFR Signaling MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236262 0.951 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. SIGNOR-236455 0.489 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS factor protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-251525 0.2 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr. SIGNOR-235481 0.91 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-252094 0.669 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity 10090 26592448 f Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC SIGNOR-252092 0.487 SIGNOR-EGF EGFR Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-EGF EGFR Signaling EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-EGF EGFR Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 SIGNOR-236376 0.712 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 SIGNOR-EGF EGFR Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-EGF EGFR Signaling PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 t lperfetto We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation. SIGNOR-236006 0.512 SIGNOR-EGF EGFR Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-44356 0.489 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS factor protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251523 0.2 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-EGF EGFR Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-EGF EGFR Signaling FOS factor protein P01100 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity binding 10090 2516828 t The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities. SIGNOR-252087 0.951 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236416 0.749 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248675 0.951 SIGNOR-EGF EGFR Signaling mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 0.7 SIGNOR-EGF EGFR Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.72 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 SIGNOR-EGF EGFR Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-EGF EGFR Signaling SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44870 0.648 SIGNOR-EGF EGFR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-EGF EGFR Signaling CBLB protein Q13191 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11375397 t lperfetto Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. SIGNOR-236519 0.744 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236404 0.749 SIGNOR-EGF EGFR Signaling HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 8052307 t lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-236443 0.922 SIGNOR-EGF EGFR Signaling ERRFI1 protein Q9UJM3 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates binding 10116 11003669 t gcesareni These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer) SIGNOR-186198 0.662 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 f JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion SIGNOR-235870 0.596 SIGNOR-EGF EGFR Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-EGF EGFR Signaling JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.786 SIGNOR-EGF EGFR Signaling EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236400 0.749 SIGNOR-EGF EGFR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236258 0.951 SIGNOR-EGF EGFR Signaling NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 11157752 t lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. SIGNOR-235947 0.695 SIGNOR-EGF EGFR Signaling ELK1 factor protein P19419 UNIPROT Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions SIGNOR-233471 0.7 SIGNOR-EGF EGFR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252082 0.2 SIGNOR-EGF EGFR Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-EGF EGFR Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-EGF EGFR Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-EGF EGFR Signaling PTPN11 protein Q06124 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not SIGNOR-236424 0.865 SIGNOR-EGF EGFR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-EGF EGFR Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-EGF EGFR Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-EGF EGFR Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-235881 0.965 SIGNOR-EI EBV infection TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252063 0.616 SIGNOR-EI EBV infection TGFB1 extracellular protein P01137 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 f gcesareni These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival SIGNOR-179179 0.379 SIGNOR-EI EBV infection IGF1R receptor protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-252690 0.685 SIGNOR-EI EBV infection MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly, SIGNOR-43996 0.427 SIGNOR-EI EBV infection IFNAR receptor complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 SIGNOR-EI EBV infection MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway SIGNOR-55710 0.637 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 26428373 f scontino AP1 is a dimeric transcription factor composed of members of the Jun and Fos protooncoprotein families. AP1 was found induced by LMP1 through the JNK signaling cascade, involving JNK1-mediated phosphorylation and activation of c-Jun. JNK1 activation critically relies on CTAR2 and its P379VQLSYY motif. It has long been unclear which signaling mediators at CTAR2 are involved in JNK activation. SIGNOR-267617 0.2 SIGNOR-EI EBV infection Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 SIGNOR-EI EBV infection TNF extracellular protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-252733 0.327 SIGNOR-EI EBV infection TLR2 receptor protein O60603 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266745 0.716 SIGNOR-EI EBV infection TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-EI EBV infection IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249506 0.694 SIGNOR-EI EBV infection NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.362 SIGNOR-EI EBV infection TYK2 protein P29597 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity. SIGNOR-246943 0.768 SIGNOR-EI EBV infection MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21133840 t miannu RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256024 0.713 SIGNOR-EI EBV infection CSK protein P41240 UNIPROT LYN protein P07948 UNIPROT down-regulates phosphorylation Tyr508 YTATEGQyQQQP 9606 BTO:0000776 15626731 t gcesareni Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts SIGNOR-132912 0.511 SIGNOR-EI EBV infection STAT1 factor protein P42224 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 t lperfetto Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease. SIGNOR-217418 0.464 SIGNOR-EI EBV infection EBV gH:gL:gp42 extracellular complex SIGNOR-C403 SIGNOR HLA-DRB1 protein P01911 UNIPROT up-regulates activity binding 9606 BTO:0000776 8764069 t scontino In EBV, the gH and gL proteins form a stable complex with a third glycoprotein, termed gp42, the product of the BZLF2 open reading frame, that appears to play a role in the infection of specific cells by EBV. The extracellular domain of BZLF2 binds specifically to a b-chain allele of the major histocompatibility complex (MHC) class II HLA-DR locus SIGNOR-266629 0.2 SIGNOR-EI EBV infection EBV gH:gL:gp42 extracellular complex SIGNOR-C403 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates activity binding 9606 BTO:0000776 11864610 t scontino The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. The gp42 binds HLA-DR1 using a surface site SIGNOR-266628 0.2 SIGNOR-EI EBV infection UBE2I protein P63279 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates activity sumoylation Lys452 EKSLVLVkLEPWLCR 9606 BTO:0002181 22951831 t scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. SIGNOR-266837 0.294 SIGNOR-EI EBV infection HLA-DRA protein P01903 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 f scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. SIGNOR-266630 0.7 SIGNOR-EI EBV infection IRF7 factor protein Q92985 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16612387 f miannu Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-263128 0.2 SIGNOR-EI EBV infection AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates activity sumoylation 9606 BTO:0002181 22951831 t scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. SIGNOR-266951 0.2 SIGNOR-EI EBV infection BZLF2 extracellular protein P03205 UNIPROT EBV gH:gL:gp42 extracellular complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 t scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. SIGNOR-266625 0.2 SIGNOR-EI EBV infection JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 f miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. SIGNOR-260178 0.7 SIGNOR-EI EBV infection gH extracellular protein P03231 UNIPROT EBV gH:gL:gp42 extracellular complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 t scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. SIGNOR-266626 0.2 SIGNOR-EI EBV infection IGF1R receptor protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 f lperfetto The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation SIGNOR-64676 0.353 SIGNOR-EI EBV infection IGF1 extracellular protein P05019 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 0.955 SIGNOR-EI EBV infection IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-EI EBV infection TLR2 receptor protein O60603 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266746 0.634 SIGNOR-EI EBV infection IFNAR receptor complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 SIGNOR-EI EBV infection NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-EI EBV infection MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 f gcesareni These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells. SIGNOR-67321 0.531 SIGNOR-EI EBV infection TGFB1 extracellular protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 t lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. SIGNOR-252729 0.268 SIGNOR-EI EBV infection TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 14530355 t lperfetto Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling SIGNOR-118458 0.812 SIGNOR-EI EBV infection AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-EI EBV infection CR2 receptor protein P20023 UNIPROT CD19 receptor protein P15391 UNIPROT up-regulates activity binding 9606 BTO:0000776 31732528 t scontino Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. SIGNOR-266642 0.777 SIGNOR-EI EBV infection IFNAR receptor complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260146 0.8 SIGNOR-EI EBV infection BGLF4 protein P13288 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity phosphorylation Thr180 SPSLDNPtPFPNLGP 9606 BTO:0002181 19052084 t scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. SIGNOR-266649 0.2 SIGNOR-EI EBV infection CD19 receptor protein P15391 UNIPROT LYN protein P07948 UNIPROT up-regulates activity binding 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242894 0.765 SIGNOR-EI EBV infection NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. SIGNOR-260346 0.7 SIGNOR-EI EBV infection PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-EI EBV infection BGLF4 protein P13288 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 BTO:0002181 19052084 t scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. SIGNOR-266648 0.2 SIGNOR-EI EBV infection IRF3 factor protein Q14653 UNIPROT Interferon_Production phenotypesList phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-126962 0.7 SIGNOR-EI EBV infection IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-EI EBV infection NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR EBNA1 protein P03211 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29659505 t scontino We found that EBV-encoded Qp-EBNA1 can be upregulated by NF-κB, while EBNA1 protein expression has been shown to negatively regulate NF-κB activation by inhibiting IKKα/β phosphorylation SIGNOR-266803 0.2 SIGNOR-EI EBV infection IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR STAT1 factor protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 0.666 SIGNOR-EI EBV infection BGLF4 protein P13288 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity phosphorylation Ser123 DFSQPDTsPDTNGGG 9606 BTO:0002181 19052084 t scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. SIGNOR-266647 0.2 SIGNOR-EI EBV infection JAK2 protein O60674 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 0.801 SIGNOR-EI EBV infection BRLF1 protein P03209 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 t scontino EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs. SIGNOR-266644 0.2 SIGNOR-EI EBV infection MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17563747 t lperfetto Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. SIGNOR-236346 0.298 SIGNOR-EI EBV infection NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon_Production phenotypesList phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-216322 0.7 SIGNOR-EI EBV infection BRLF1 protein P03209 UNIPROT IFNB1 extracellular protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 t scontino Epstein-Barr Virus BRLF1 Inhibits Transcription of IRF3 and IRF7 and Suppresses Induction of Interferon-β. These results suggest that EBV Rta is capable of regulating the activation of the IFN-β promoter. SIGNOR-266646 0.2 SIGNOR-EI EBV infection CD19 receptor protein P15391 UNIPROT B_cell_maturation phenotypesList phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 f lperfetto CD19 is a crucial regulator of B cell activation. SIGNOR-242888 0.7 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 26428373 f scontino Soon, it has been recognized that TES1 and 2 coincide with two regions named C-terminal activating regions (CTAR) 1 and 2, respectively, that are responsible for interaction of LMP1 with cellular signaling molecules. Early studies revealed that both CTAR1 and CTAR2 contribute to the activation of NF-κB, Later, it became evident that CTAR1 primarily activates the non-canonical NF-κB pathway, while CTAR2 is responsible for canonical NF-κB activation. SIGNOR-267616 0.2 SIGNOR-EI EBV infection LMP2 protein P13285 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR down-regulates quantity by destabilization 9606 19718044 f scontino The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation.LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1. SIGNOR-266824 0.2 SIGNOR-EI EBV infection BPLF1 protein P03186 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity deubiquitination 9606 24586164 t scontino In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes. SIGNOR-266744 0.2 SIGNOR-EI EBV infection BPLF1 protein P03186 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity deubiquitination 9606 24586164 t scontino In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes. SIGNOR-266743 0.2 SIGNOR-EI EBV infection EBNA1 protein P03211 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity 9606 29659505 f scontino EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity SIGNOR-266802 0.2 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT UBE2I protein P63279 UNIPROT up-regulates activity binding 9606 BTO:0002181 22951831 t scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. SIGNOR-266838 0.2 SIGNOR-EI EBV infection TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-EI EBV infection HLA-DRB1 protein P01911 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 f scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. SIGNOR-266631 0.7 SIGNOR-EI EBV infection TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-EI EBV infection LMP2 protein P13285 UNIPROT IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR down-regulates quantity by destabilization 9606 19718044 f scontino The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation. LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1. SIGNOR-266825 0.2 SIGNOR-EI EBV infection BZLF1 protein P03206 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates activity binding 9606 BTO:0002181 20381110 t scontino We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters SIGNOR-266643 0.2 SIGNOR-EI EBV infection BPLF1 protein P03186 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 23365429 t scontino EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication. SIGNOR-266739 0.2 SIGNOR-EI EBV infection BLLF1 protein P03200 UNIPROT CR2 receptor protein P20023 UNIPROT up-regulates activity binding 9606 BTO:0000776 18786993 t scontino The binding of the Epstein-Barr virus glycoprotein gp350 by complement receptor type 2 (CR2) is critical for viral attachment to B lymphocytes. SIGNOR-266624 0.2 SIGNOR-EI EBV infection AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-EI EBV infection EBNA1 protein P03211 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity destabilization 9606 BTO:0000192 17486072 f scontino The studies described above show that SMAD2 protein levels are reduced by EBNA1 with consequent attenuation of SMAD2 activation in response to TGFβ1. This analysis confirmed the stability of the EBNA1 protein and revealed that the SMAD2 protein is more rapidly degraded in Ad/AH cells expressing EBNA1 as compared to the control cells. SIGNOR-267615 0.2 SIGNOR-EI EBV infection TNF extracellular protein P01375 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 f andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 0.666 SIGNOR-EI EBV infection TNF extracellular protein P01375 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates activity 9606 23685857 f Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis SIGNOR-258988 0.7 SIGNOR-EI EBV infection STAT3 protein P40763 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263821 0.7 SIGNOR-EI EBV infection CD19 receptor protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-252670 0.497 SIGNOR-EI EBV infection LYN protein P07948 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9534 11514608 t BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain. SIGNOR-251403 0.39 SIGNOR-EI EBV infection MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 t miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity SIGNOR-260160 0.92 SIGNOR-EI EBV infection EBNA1 protein P03211 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007;BTO:0006136 17486072 f scontino EBNA1 enhances the expression and activity of STAT1. EBNA1 also induced STAT1 expression, with associated enhancement of IFNγ-induced activation. The ability of EBNA1 to enhance IFNγ-induced STAT1 signaling was observed at the protein level by enhanced nuclear translocation of STAT1 (Figure 3b) and at the transcriptional level. SIGNOR-267614 0.2 SIGNOR-EI EBV infection BGLF5 protein P03217 UNIPROT TLR2 receptor protein O60603 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002181 26428381 t scontino The RNA degradation induced by EBV BGLF5 can affect immunologically relevant proteins, including TLR2. Alkaline exonuclease involved in host shutoff, downregulates TLR2. SIGNOR-266741 0.2 SIGNOR-EI EBV infection JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.812 SIGNOR-EI EBV infection IGF1R receptor protein P08069 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 10090 BTO:0000165 11715022 f lperfetto we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. SIGNOR-244403 0.401 SIGNOR-EI EBV infection IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-EI EBV infection LF2 protein P0C725 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates activity binding 9606 BTO:0002181 18987133 t scontino EBV LF2 tegument protein specifically interacts with the central inhibitory association domain of IRF7, and this interaction leads to inhibition of the dimerization of IRF7, which suppresses IFN-alpha production and IFN-mediated immunity. SIGNOR-266632 0.2 SIGNOR-EI EBV infection USP7 protein Q93009 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53. SIGNOR-139456 0.732 SIGNOR-EI EBV infection STAT1 factor protein P42224 UNIPROT IRF7 factor protein Q92985 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 16628196 f miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. SIGNOR-255231 0.503 SIGNOR-EI EBV infection NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-EI EBV infection JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249492 0.669 SIGNOR-EI EBV infection TLR9 receptor protein Q9NR96 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266748 0.458 SIGNOR-EI EBV infection gL extracellular protein P03212 UNIPROT EBV gH:gL:gp42 extracellular complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 t scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. SIGNOR-266627 0.2 SIGNOR-EI EBV infection TLR9 receptor protein Q9NR96 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266749 0.456 SIGNOR-EI EBV infection BRLF1 protein P03209 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 t scontino EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs. SIGNOR-266645 0.2 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9606 26428373 f scontino Activation of the PI3-K/AKT pathway was first linked to LMP1 in the year 2003. Although it is still unclear whether this interaction is direct, expression of LMP1 CTAR1 caused (i) an enrichment of the PI3-K substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3) in the plasma membrane and (ii) the phosphorylation and activation of AKT kinase, also known as protein kinase B, at serine 473. SIGNOR-267618 0.2 SIGNOR-EI EBV infection BGLF5 protein P03217 UNIPROT TLR9 receptor protein Q9NR96 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 21191071 t scontino The EBV lytic-phase protein BGLF5 reduces TLR9 expression through mRNA degradation. We established that the EBV early protein BGLF5 degrades TLR9 mRNA in vitro, providing a mechanism for its contribution to TLR9 downregulation. SIGNOR-266633 0.2 SIGNOR-EI EBV infection LMP1 protein P03230 UNIPROT TLR9 receptor protein Q9NR96 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000726 20980631 f scontino We determined that the EBV oncoprotein latent membrane protein 1 (LMP1) is a strong inhibitor of TLR9 transcription. These data show that the oncoprotein LMP1 downregulates TLR9 promoter activity in B cells. SIGNOR-266804 0.2 SIGNOR-ES ErbB receptors in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-ES ErbB receptors in cancer ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256168 0.772 SIGNOR-ES ErbB receptors in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-ES ErbB receptors in cancer ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 14967450 t miannu All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor SIGNOR-256162 0.2 SIGNOR-ES ErbB receptors in cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-ES ErbB receptors in cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-ES ErbB receptors in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-ES ErbB receptors in cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-ES ErbB receptors in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-ES ErbB receptors in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-ES ErbB receptors in cancer HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-ES ErbB receptors in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-ES ErbB receptors in cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-ES ErbB receptors in cancer Neuregulin extracellular proteinfamily SIGNOR-PF37 SIGNOR ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity binding 9606 18415007 t miannu The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases SIGNOR-256161 0.906 SIGNOR-ES ErbB receptors in cancer HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-ES ErbB receptors in cancer SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-ES ErbB receptors in cancer PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-ES ErbB receptors in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-ES ErbB receptors in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-ES ErbB receptors in cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-ES ErbB receptors in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-ES ErbB receptors in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 0.599 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236777 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 t lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis GATA2 factor protein P23769 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates activity 9606 20510530 t fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis SIGNOR-132949 0.382 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXO1 factor protein Q12778 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236764 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 factor protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 t Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254974 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252691 0.599 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXO1 factor protein Q12778 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 f lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. SIGNOR-218013 0.566 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXO1 factor protein Q12778 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 f fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-178281 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 t lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252693 0.599 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 factor protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-244271 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXA2 factor protein Q9Y261 UNIPROT DLK1 receptor protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 t Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. SIGNOR-254971 0.342 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXO1 factor protein Q12778 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254981 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis GATA2 factor protein P23769 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78659 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 factor protein Q9Y261 UNIPROT down-regulates phosphorylation 9606 14500912 t �Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254978 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.785 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis DLK1 receptor protein P80370 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 f fspada We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. SIGNOR-197634 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PPARG factor protein P37231 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 t miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 0.8 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.932 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis DLK1 receptor protein P80370 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 f This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. SIGNOR-254980 0.7 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 0.2 SIGNOR-FapINS FAP: Insulin-mediated adipogenesis FOXO1 factor protein Q12778 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. SIGNOR-254977 0.7 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACLY protein P53396 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267103 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ME1 protein P48163 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267723 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis malonyl-CoA smallmolecule CHEBI:15531 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268090 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267900 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267905 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis HACD proteinfamily SIGNOR-PF86 SIGNOR ELOVL proteinfamily SIGNOR-PF93 SIGNOR up-regulates activity binding 18554506 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267915 0.2 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267102 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACSL5 protein Q9ULC5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity chemical modification 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267712 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FASN protein P49327 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267208 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267100 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 33064660 t miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. SIGNOR-267721 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FASN protein P49327 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267759 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACSL1 protein P33121 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity chemical modification 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267877 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267107 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates binding 9606 17452323 t Carnitine palmitoyltransferase 1 (CPT1) catalyzes the conversion of palmitoyl-CoA to palmitoylcarnitine in the presence of l-carnitine, thus facilitating the entry of fatty acids to mitochondria, in a process that is physiologically inhibited by malonyl-CoA SIGNOR-267758 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACACA protein Q13085 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267109 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FASN protein P49327 UNIPROT hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity chemical modification 9606 12689621 t An organizational model for animal FAS was proposed in which the two subunits depicted in domains I, II, and III were arranged in an antiparallel fashion, thereby generating two sites for palmitate synthesis. Initiation of the series of condensation reactions leading to the production of palmitic acid requires the translocation of one acetyl and seven malonyl moieties, from CoA thioester to the phosphopantetheine thiol of the ACP domain. SIGNOR-267373 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267903 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis HACD proteinfamily SIGNOR-PF86 SIGNOR very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity chemical modification 9606 18554507 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267918 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FADS1 protein O60427 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267911 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ELOVL proteinfamily SIGNOR-PF93 SIGNOR 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267902 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FADS3 protein Q9Y5Q0 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267913 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity precursor of 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267711 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis SLC25A1 receptor protein P53007 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity relocalization 9606 29651165 t SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate SIGNOR-267289 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267904 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis pyruvate smallmolecule CHEBI:15361 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates activity 9606 18613815 f Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. SIGNOR-267384 0.7 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267906 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266281 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267055 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity precursor of 9606 18554507 t miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. SIGNOR-267916 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis CPT1A protein P50416 UNIPROT Fatty_acid_oxidation phenotypesList phenotype SIGNOR-PH129 SIGNOR up-regulates activity 9606 31900483 f As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria SIGNOR-267757 0.7 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis malonyl-CoA smallmolecule CHEBI:15531 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267210 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis hexadecanoic acid smallmolecule CHEBI:15756 ChEBI palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity precursor of 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267876 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FADS2 protein O95864 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267912 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis FADS6 protein Q8N9I5 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267914 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266285 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis ACACB protein O00763 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267110 0.8 SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267108 0.8 SIGNOR-Fibrosis Fibrosis Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 24168260 f miannu We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis. SIGNOR-260447 0.2 SIGNOR-Fibrosis Fibrosis TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-Fibrosis Fibrosis Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT MAS1 receptor protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 SIGNOR-Fibrosis Fibrosis AGTR2 receptor protein P50052 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 32201502 f MIANNU AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth SIGNOR-260232 0.7 SIGNOR-Fibrosis Fibrosis SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 t miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression SIGNOR-260437 0.593 SIGNOR-Fibrosis Fibrosis Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT up-regulates activity binding 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260226 0.2 SIGNOR-Fibrosis Fibrosis AGTR1 receptor protein P30556 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 SIGNOR-Fibrosis Fibrosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260446 0.7 SIGNOR-Fibrosis Fibrosis REN extracellular protein P00797 UNIPROT Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260225 0.2 SIGNOR-Fibrosis Fibrosis SMAD7 protein O15105 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 30017632 t miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). SIGNOR-260438 0.781 SIGNOR-Fibrosis Fibrosis EP300 factor protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 t miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. SIGNOR-260431 0.726 SIGNOR-Fibrosis Fibrosis Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR2 receptor protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 SIGNOR-Fibrosis Fibrosis TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-Fibrosis Fibrosis Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR1 receptor protein P30556 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260238 0.2 SIGNOR-Fibrosis Fibrosis TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-Fibrosis Fibrosis MAS1 receptor protein P04201 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 SIGNOR-Fibrosis Fibrosis TGFBR1 receptor protein P36897 UNIPROT SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 f miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. SIGNOR-260590 0.45 SIGNOR-Fibrosis Fibrosis ACE receptor protein P12821 UNIPROT Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260236 0.2 SIGNOR-Fibrosis Fibrosis TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-Fibrosis Fibrosis TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-Fibrosis Fibrosis AGT extracellular protein P01019 UNIPROT REN extracellular protein P00797 UNIPROT up-regulates activity binding 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260224 0.927 SIGNOR-Fibrosis Fibrosis SMAD3 protein P84022 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 SIGNOR-Fibrosis Fibrosis SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-Fibrosis Fibrosis Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE receptor protein P12821 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260231 0.2 SIGNOR-Fibrosis Fibrosis AGTR1 receptor protein P30556 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260234 0.7 SIGNOR-Fibrosis Fibrosis SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260425 0.475 SIGNOR-Fibrosis Fibrosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260445 0.7 SIGNOR-Fibrosis Fibrosis SERPINE1 extracellular protein P05121 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 f miannu Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. SIGNOR-260588 0.7 SIGNOR-Fibrosis Fibrosis BCL2L11 protein O43521 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 SIGNOR-Fibrosis Fibrosis ACE2 receptor protein Q9BYF1 UNIPROT Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 SIGNOR-Fibrosis Fibrosis TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-FIIA FLT3-ITD in AML MYC factor protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 f USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261560 0.513 SIGNOR-FIIA FLT3-ITD in AML BAD protein Q92934 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256259 0.7 SIGNOR-FIIA FLT3-ITD in AML ZBTB16 factor protein Q05516 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest. SIGNOR-261685 0.7 SIGNOR-FIIA FLT3-ITD in AML CEBPA factor protein P49715 UNIPROT SPI1 factor protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14592841 t Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD SIGNOR-261531 0.549 SIGNOR-FIIA FLT3-ITD in AML DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 t amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. SIGNOR-134285 0.799 SIGNOR-FIIA FLT3-ITD in AML MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-FIIA FLT3-ITD in AML RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.643 SIGNOR-FIIA FLT3-ITD in AML STAT5A factor protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0004479 29507660 f irozzo FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. SIGNOR-255733 0.428 SIGNOR-FIIA FLT3-ITD in AML SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 f lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-242628 0.708 SIGNOR-FIIA FLT3-ITD in AML MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162322 0.627 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15574429 f Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity SIGNOR-261532 0.374 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 10090 BTO:0001516 14981546 t These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261522 0.448 SIGNOR-FIIA FLT3-ITD in AML STAT5A factor protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261551 0.641 SIGNOR-FIIA FLT3-ITD in AML TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-FIIA FLT3-ITD in AML MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162314 0.627 SIGNOR-FIIA FLT3-ITD in AML MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162318 0.627 SIGNOR-FIIA FLT3-ITD in AML BAD protein Q92934 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256260 0.7 SIGNOR-FIIA FLT3-ITD in AML BCL2L1 protein Q07817 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 f fcortellessa Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition SIGNOR-261683 0.7 SIGNOR-FIIA FLT3-ITD in AML NOTCH1 protein P46531 UNIPROT HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 f lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. SIGNOR-183507 0.764 SIGNOR-FIIA FLT3-ITD in AML SPI1 factor protein P17947 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 f lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. SIGNOR-249633 0.7 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT NCOR2 factor protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261538 0.262 SIGNOR-FIIA FLT3-ITD in AML CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-FIIA FLT3-ITD in AML ZBTB16 factor protein Q05516 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF overexpression leads to apoptosis. SIGNOR-261686 0.7 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 15769897 t we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y SIGNOR-261540 0.432 SIGNOR-FIIA FLT3-ITD in AML RELA factor protein Q04206 UNIPROT NCOR2 factor protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 t Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export. SIGNOR-261539 0.415 SIGNOR-FIIA FLT3-ITD in AML PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax SIGNOR-259418 0.2 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT FZD4 receptor protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002882 15650056 f AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3. SIGNOR-261533 0.2 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0001516 12796379 t FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. SIGNOR-261516 0.594 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT ZBTB16 factor protein Q05516 UNIPROT down-regulates activity 10090 BTO:0002181 14982881 f We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. SIGNOR-261537 0.322 SIGNOR-FIIA FLT3-ITD in AML PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-FIIA FLT3-ITD in AML STAT5A factor protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 f Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. SIGNOR-261518 0.333 SIGNOR-FIIA FLT3-ITD in AML HES1 factor protein Q14469 UNIPROT FLT3 receptor protein P36888 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25234168 t We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. SIGNOR-261563 0.2 SIGNOR-FIIA FLT3-ITD in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252938 0.7 SIGNOR-FIIA FLT3-ITD in AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT PTPRJ receptor protein Q12913 UNIPROT down-regulates activity 10090 22438257 f Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels. SIGNOR-261553 0.507 SIGNOR-FIIA FLT3-ITD in AML FZD4 receptor protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258955 0.594 SIGNOR-FIIA FLT3-ITD in AML PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT PARP1 factor protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  SIGNOR-261554 0.254 SIGNOR-FIIA FLT3-ITD in AML USP22 protein Q9UPT9 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 26049753 t USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. SIGNOR-261561 0.555 SIGNOR-FIIA FLT3-ITD in AML FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SIGNOR-FIIA FLT3-ITD in AML PTPRJ receptor protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 t gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. SIGNOR-252727 0.265 SIGNOR-FIIA FLT3-ITD in AML EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-252671 0.772 SIGNOR-FIIA FLT3-ITD in AML NOTCH1 protein P46531 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 f flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages SIGNOR-241998 0.7 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 f These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261521 0.298 SIGNOR-FIIA FLT3-ITD in AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-FIIA FLT3-ITD in AML FLT3LG extracellular protein P49771 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), SIGNOR-99750 0.88 SIGNOR-FIIA FLT3-ITD in AML NCOR2 factor protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t Ncor2 is a Skip corepressor gcesareni Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt. SIGNOR-74227 0.57 SIGNOR-FIIA FLT3-ITD in AML TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18192505 f Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity SIGNOR-261536 0.2 SIGNOR-FIIA FLT3-ITD in AML SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins SIGNOR-108499 0.581 SIGNOR-FIIA FLT3-ITD in AML PIM1 protein P11309 UNIPROT FLT3 receptor protein P36888 UNIPROT up-regulates quantity phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. SIGNOR-259927 0.437 SIGNOR-FIIA FLT3-ITD in AML FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 f Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD SIGNOR-261529 0.624 SIGNOR-FIIA FLT3-ITD in AML SIRT1 protein Q96EB6 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization deacetylation 9606 25280219 t SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites SIGNOR-261562 0.798 SIGNOR-FIIA FLT3-ITD in AML PIM1 protein P11309 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 t FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells SIGNOR-261557 0.684 SIGNOR-FIIA FLT3-ITD in AML AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.909 SIGNOR-FIIA FLT3-ITD in AML RAD51 protein Q06609 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells SIGNOR-251508 0.7 SIGNOR-FIIA FLT3-ITD in AML PTPN6 protein P29350 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation. SIGNOR-59965 0.426 SIGNOR-FIIA FLT3-ITD in AML AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. SIGNOR-244314 0.2 SIGNOR-FIIA FLT3-ITD in AML STAT5A factor protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261552 0.268 SIGNOR-FIIA FLT3-ITD in AML NOTCH receptor proteinfamily SIGNOR-PF30 SIGNOR HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32195003 f Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR SIGNOR-261534 0.2 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252834 0.909 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.747 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-244595 0.2 SIGNOR-FIS FLT3-ITD signaling mTORC2 complex SIGNOR-C2 SIGNOR MYC factor protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256171 0.364 SIGNOR-FIS FLT3-ITD signaling STAT5A factor protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 t FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261552 0.268 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.785 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158636 0.839 SIGNOR-FIS FLT3-ITD signaling CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner SIGNOR-133375 0.837 SIGNOR-FIS FLT3-ITD signaling XPO1 protein O14980 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates activity relocalization 9606 17891139 t miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. SIGNOR-260067 0.572 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115348 0.839 SIGNOR-FIS FLT3-ITD signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250101 0.754 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.909 SIGNOR-FIS FLT3-ITD signaling TLR4 receptor protein O00206 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-261930 0.445 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 t gcesareni Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling. SIGNOR-90608 0.478 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75629 0.785 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-74835 0.785 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.747 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage. SIGNOR-126757 0.839 SIGNOR-FIS FLT3-ITD signaling MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-FIS FLT3-ITD signaling STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation -1 14976552 t lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). SIGNOR-242602 0.591 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153479 0.785 SIGNOR-FIS FLT3-ITD signaling MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-FIS FLT3-ITD signaling STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-FIS FLT3-ITD signaling RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. SIGNOR-209871 0.295 SIGNOR-FIS FLT3-ITD signaling BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 factor protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-244673 0.2 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 33081032 t miannu GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371. SIGNOR-263513 0.367 SIGNOR-FIS FLT3-ITD signaling PIM1 protein P11309 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 t FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells SIGNOR-261557 0.684 SIGNOR-FIS FLT3-ITD signaling TLR4 receptor protein O00206 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-261929 0.508 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 SIGNOR-77144 0.785 SIGNOR-FIS FLT3-ITD signaling AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 20660302 f P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity SIGNOR-255951 0.284 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9122197 f gcesareni P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis SIGNOR-47541 0.742 SIGNOR-FIS FLT3-ITD signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252837 0.909 SIGNOR-FIS FLT3-ITD signaling BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-199504 0.857 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74823 0.785 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-FIS FLT3-ITD signaling CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245462 0.885 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.909 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-FIS FLT3-ITD signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-FIS FLT3-ITD signaling MAPK14 protein Q16539 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0001255 12839928 f miannu Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. SIGNOR-263511 0.654 SIGNOR-FIS FLT3-ITD signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252833 0.909 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 14963330 t lperfetto Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-178690 0.742 SIGNOR-FIS FLT3-ITD signaling IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 t gcesareni Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-192614 0.266 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. SIGNOR-167152 0.839 SIGNOR-FIS FLT3-ITD signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28138032 f miannu Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis. SIGNOR-263069 0.2 SIGNOR-FIS FLT3-ITD signaling RB1 protein P06400 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-262533 0.7 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153483 0.785 SIGNOR-FIS FLT3-ITD signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. SIGNOR-242616 0.7 SIGNOR-FIS FLT3-ITD signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-FIS FLT3-ITD signaling IKBKB protein O14920 UNIPROT FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252947 0.673 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.909 SIGNOR-FIS FLT3-ITD signaling MAPKAPK2 protein P49137 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-153944 0.678 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.785 SIGNOR-FIS FLT3-ITD signaling LY2603618 extracellular chemical CID:11955855 ChEBI CHEK1 protein O14757 UNIPROT down-regulates activity chemical inhibition 9606 33261142 t miannu Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. SIGNOR-262538 0.8 SIGNOR-FIS FLT3-ITD signaling MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 t gcesareni However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes. SIGNOR-157548 0.295 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158632 0.839 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 t gcesareni DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation SIGNOR-167156 0.839 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 SIGNOR-153908 0.435 SIGNOR-FIS FLT3-ITD signaling AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t gcesareni The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. SIGNOR-124365 0.443 SIGNOR-FIS FLT3-ITD signaling CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. SIGNOR-250747 0.738 SIGNOR-FIS FLT3-ITD signaling 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity 10090 24260231 f miannu Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells. SIGNOR-263050 0.303 SIGNOR-FIS FLT3-ITD signaling PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-178615 0.398 SIGNOR-FIS FLT3-ITD signaling TLR4 receptor protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 28137827 t miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. SIGNOR-263652 0.432 SIGNOR-FIS FLT3-ITD signaling PARP1 factor protein P09874 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity relocalization 9606 17891139 t miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. SIGNOR-261321 0.582 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.785 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc SIGNOR-118844 0.709 SIGNOR-FIS FLT3-ITD signaling NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.909 SIGNOR-FIS FLT3-ITD signaling ATR protein Q13535 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. SIGNOR-115134 0.73 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.785 SIGNOR-FIS FLT3-ITD signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. SIGNOR-244780 0.2 SIGNOR-FIS FLT3-ITD signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-244180 0.2 SIGNOR-FIS FLT3-ITD signaling NOTCH1 protein P46531 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 f gcesareni We identified c-myc as a direct target of notch1 SIGNOR-147944 0.659 SIGNOR-FIS FLT3-ITD signaling IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-FIS FLT3-ITD signaling PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55306 0.709 SIGNOR-FIS FLT3-ITD signaling KU-55933 extracellular chemical CID:5278396 ChEBI ATM protein Q13315 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 28341201 t miannu KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. SIGNOR-262536 0.8 SIGNOR-FIS FLT3-ITD signaling sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition 9606 7566123 t Monia Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. SIGNOR-261074 0.8 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201530 0.96 SIGNOR-FIS FLT3-ITD signaling MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188408 0.747 SIGNOR-FIS FLT3-ITD signaling PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-164642 0.497 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 SIGNOR-142103 0.254 SIGNOR-FIS FLT3-ITD signaling RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-110917 0.367 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites SIGNOR-153475 0.785 SIGNOR-FIS FLT3-ITD signaling CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-262532 0.7 SIGNOR-FIS FLT3-ITD signaling MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154783 0.606 SIGNOR-FIS FLT3-ITD signaling PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 t miannu Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells SIGNOR-250270 0.608 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 t Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis SIGNOR-33922 0.742 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 8355 10775268 f lperfetto Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter SIGNOR-76984 0.471 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential, SIGNOR-124047 0.543 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor SIGNOR-146915 0.739 SIGNOR-FIS FLT3-ITD signaling ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.5 SIGNOR-FIS FLT3-ITD signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.747 SIGNOR-FIS FLT3-ITD signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-217008 0.634 SIGNOR-FIS FLT3-ITD signaling BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.928 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.785 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates activity phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 t lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) SIGNOR-124043 0.543 SIGNOR-FIS FLT3-ITD signaling quizartinib chemical CHEBI:90217 ChEBI FLT3 receptor protein P36888 UNIPROT down-regulates activity chemical inhibition -1 19754199 t Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. SIGNOR-255666 0.8 SIGNOR-FIS FLT3-ITD signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-FIS FLT3-ITD signaling PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3 SIGNOR-195766 0.463 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 t miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. SIGNOR-260124 0.425 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 t GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant SIGNOR-251233 0.682 SIGNOR-FIS FLT3-ITD signaling 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 ChEBI GSK3B protein P49841 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000183 31562256 t miannu Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines SIGNOR-262539 0.8 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT CEBPB factor protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 f lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required SIGNOR-250573 0.584 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.909 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SIGNOR-FIS FLT3-ITD signaling AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-FIS FLT3-ITD signaling AMPK complex SIGNOR-C15 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252880 0.396 SIGNOR-FIS FLT3-ITD signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT PARP1 factor protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  SIGNOR-261554 0.254 SIGNOR-FIS FLT3-ITD signaling CEBPB factor protein P17676 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 t Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. SIGNOR-254044 0.2 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.371 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.545 SIGNOR-FIS FLT3-ITD signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity binding 9606 15126506 t lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity SIGNOR-252894 0.536 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. SIGNOR-251474 0.2 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75645 0.785 SIGNOR-FIS FLT3-ITD signaling BAD protein Q92934 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256259 0.7 SIGNOR-FIS FLT3-ITD signaling PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.785 SIGNOR-FIS FLT3-ITD signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 f miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 0.7 SIGNOR-FIS FLT3-ITD signaling MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-FIS FLT3-ITD signaling STAT5A factor protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 t Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261517 0.389 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115344 0.839 SIGNOR-FIS FLT3-ITD signaling SB 203580 extracellular chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 10702313 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-75389 0.8 SIGNOR-FIS FLT3-ITD signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 0.7 SIGNOR-FIS FLT3-ITD signaling GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0001516 23246379 t Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation SIGNOR-255946 0.341 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75637 0.785 SIGNOR-FIS FLT3-ITD signaling olaparib chemical CHEBI:83766 ChEBI PARP1 factor protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195016 0.8 SIGNOR-FIS FLT3-ITD signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-134185 0.928 SIGNOR-FIS FLT3-ITD signaling AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 t miannu AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling. SIGNOR-262535 0.547 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.785 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-FIS FLT3-ITD signaling RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137255 0.2 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t Cytosolic p53 amattioni P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization. SIGNOR-140242 0.742 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-252824 0.909 SIGNOR-FIS FLT3-ITD signaling MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 t gcesareni Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin. SIGNOR-178603 0.295 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115340 0.839 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262522 0.2 SIGNOR-FIS FLT3-ITD signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 f Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. SIGNOR-261520 0.295 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.909 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163110 0.841 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.909 SIGNOR-FIS FLT3-ITD signaling Selinexor chemical CID:71481097 ChEBI XPO1 protein O14980 UNIPROT down-regulates activity chemical inhibition 9606 30510142 t miannu Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs. SIGNOR-262537 0.8 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-FIS FLT3-ITD signaling PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t irozzo Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255982 0.646 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-FIS FLT3-ITD signaling S100A9 protein P06702 UNIPROT TLR4 receptor protein O00206 UNIPROT up-regulates activity binding 9606 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB. SIGNOR-261918 0.526 SIGNOR-FIS FLT3-ITD signaling CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 t llicata These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 SIGNOR-153904 0.435 SIGNOR-FIS FLT3-ITD signaling RPS6KA1 protein Q15418 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-72117 0.738 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. SIGNOR-107256 0.747 SIGNOR-FIS FLT3-ITD signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 t gcesareni Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci SIGNOR-174442 0.2 SIGNOR-FIS FLT3-ITD signaling BAD protein Q92934 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002552 17000778 t lperfetto We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis SIGNOR-149815 0.338 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 f Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261519 0.437 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. SIGNOR-126753 0.839 SIGNOR-FIS FLT3-ITD signaling FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SIGNOR-FIS FLT3-ITD signaling FLT3 receptor protein P36888 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 f FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells SIGNOR-261550 0.256 SIGNOR-FIS FLT3-ITD signaling TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-121895 0.742 SIGNOR-FIS FLT3-ITD signaling wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 8162590 t gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. SIGNOR-252666 0.8 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75641 0.785 SIGNOR-FIS FLT3-ITD signaling JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo. SIGNOR-261133 0.2 SIGNOR-FIS FLT3-ITD signaling KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-FIS FLT3-ITD signaling ATR protein Q13535 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli. SIGNOR-124060 0.354 SIGNOR-FIS FLT3-ITD signaling CREB1 factor protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis SIGNOR-43927 0.434 SIGNOR-FIS FLT3-ITD signaling JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.812 SIGNOR-FIS FLT3-ITD signaling STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-FIS FLT3-ITD signaling PIM1 protein P11309 UNIPROT FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. SIGNOR-252966 0.397 SIGNOR-FIS FLT3-ITD signaling STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-FIS FLT3-ITD signaling CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-75633 0.785 SIGNOR-FIS FLT3-ITD signaling pimozide extracellular chemical CHEBI:8212 ChEBI STAT5A factor protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001545 23264850 t miannu We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis. SIGNOR-260125 0.8 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.909 SIGNOR-FIS FLT3-ITD signaling U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 9873633 t lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-244958 0.8 SIGNOR-FIS FLT3-ITD signaling IKBKB protein O14920 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-217403 0.864 SIGNOR-FIS FLT3-ITD signaling IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. SIGNOR-249365 0.919 SIGNOR-FIS FLT3-ITD signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-FIS FLT3-ITD signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 SIGNOR-FIS FLT3-ITD signaling CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-FIS FLT3-ITD signaling KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-FIS FLT3-ITD signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-FIS FLT3-ITD signaling ATM protein Q13315 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates phosphorylation Thr100 LKRLFSGtQISTIAE 9606 15073328 t lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) SIGNOR-124051 0.543 SIGNOR-FIS FLT3-ITD signaling GSK3B protein P49841 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-217430 0.381 SIGNOR-FIS FLT3-ITD signaling MTOR protein P42345 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-262534 0.727 SIGNOR-FIS FLT3-ITD signaling BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.615 SIGNOR-FM One-carbon Metabolism MTHFD1 protein P11586 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268249 0.8 SIGNOR-FM One-carbon Metabolism Glycine cleavage system complex SIGNOR-C437 SIGNOR glycine extracellular smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268238 0.8 SIGNOR-FM One-carbon Metabolism (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268233 0.8 SIGNOR-FM One-carbon Metabolism Food intake extracellular phenotype SIGNOR-PH152 SIGNOR folic acid smallmolecule CHEBI:27470 ChEBI up-regulates 9606 19706381 f lperfetto The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women. SIGNOR-268262 0.7 SIGNOR-FM One-carbon Metabolism (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-253141 0.8 SIGNOR-FM One-carbon Metabolism folic acid smallmolecule CHEBI:27470 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 BTO:0000575 19706381 t lperfetto However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1) SIGNOR-268263 0.8 SIGNOR-FM One-carbon Metabolism MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 f miannu MTHFR promotes heterochromatin maintenance at the centromeric region. SIGNOR-263889 0.7 SIGNOR-FM One-carbon Metabolism DHFR protein P00374 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268258 0.8 SIGNOR-FM One-carbon Metabolism MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI down-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253142 0.8 SIGNOR-FM One-carbon Metabolism SHMT1 protein P34896 UNIPROT glycine extracellular smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268223 0.8 SIGNOR-FM One-carbon Metabolism MTR protein Q99707 UNIPROT methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253143 0.8 SIGNOR-FM One-carbon Metabolism SHMT2 protein P34897 UNIPROT glycine extracellular smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268224 0.8 SIGNOR-FM One-carbon Metabolism MTHFD1 protein P11586 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268250 0.8 SIGNOR-FM One-carbon Metabolism 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268248 0.8 SIGNOR-FM One-carbon Metabolism L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268269 0.8 SIGNOR-FM One-carbon Metabolism MTHFR protein P42898 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity chemical modification 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268229 0.8 SIGNOR-FM One-carbon Metabolism glycine extracellular smallmolecule CHEBI:15428 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268237 0.8 SIGNOR-FM One-carbon Metabolism L-serine chemical CHEBI:17115 ChEBI glycine extracellular smallmolecule CHEBI:15428 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268222 0.8 SIGNOR-FM One-carbon Metabolism Glycine cleavage system complex SIGNOR-C437 SIGNOR carbon dioxide smallmolecule CHEBI:16526 ChEBI up-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268244 0.8 SIGNOR-FM One-carbon Metabolism SHMT2 protein P34897 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268227 0.8 SIGNOR-FM One-carbon Metabolism TYMS protein P04818 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268232 0.8 SIGNOR-FM One-carbon Metabolism homocysteine smallmolecule CHEBI:17230 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253140 0.8 SIGNOR-FM One-carbon Metabolism (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity precursor of 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268230 0.8 SIGNOR-FM One-carbon Metabolism SFXN1 protein Q9H9B4 UNIPROT L-serine chemical CHEBI:17115 ChEBI up-regulates quantity relocalization 9606 30442778 t lperfetto SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. SIGNOR-268245 0.8 SIGNOR-FM One-carbon Metabolism TYMS protein P04818 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. SIGNOR-253139 0.7 SIGNOR-FM One-carbon Metabolism (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268246 0.8 SIGNOR-FM One-carbon Metabolism MTHFD1 protein P11586 UNIPROT formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268251 0.8 SIGNOR-FM One-carbon Metabolism dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268259 0.8 SIGNOR-FM One-carbon Metabolism DHFR protein P00374 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268257 0.8 SIGNOR-FM One-carbon Metabolism Glycine cleavage system complex SIGNOR-C437 SIGNOR (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268239 0.8 SIGNOR-FM One-carbon Metabolism SHMT1 protein P34896 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268226 0.8 SIGNOR-FM One-carbon Metabolism (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268225 0.8 SIGNOR-FM One-carbon Metabolism (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268247 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 factor protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252323 0.817 SIGNOR-FSGS Focal segmental glomerulosclerosis ROS extracellular stimulus SIGNOR-ST2 SIGNOR PAX2 factor protein Q02962 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002733 16985513 f High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling. SIGNOR-252295 0.7 SIGNOR-FSGS Focal segmental glomerulosclerosis PAX2 factor protein Q02962 UNIPROT Urogenital_tract factor phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 8575306 f Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases. SIGNOR-252301 0.7 SIGNOR-FSGS Focal segmental glomerulosclerosis ACE receptor protein P12821 UNIPROT AGT extracellular protein P01019 UNIPROT up-regulates activity cleavage 9606 11076943 t gcesareni Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. SIGNOR-253326 0.776 SIGNOR-FSGS Focal segmental glomerulosclerosis NFATC1 factor protein O95644 UNIPROT PLAUR extracellular protein Q03405 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23015147 t Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. SIGNOR-253336 0.2 SIGNOR-FSGS Focal segmental glomerulosclerosis PAXIP1 protein Q6ZW49 UNIPROT PAX2 factor protein Q02962 UNIPROT up-regulates activity binding 9606 BTO:0000007 17925232 t PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex SIGNOR-251711 0.594 SIGNOR-FSGS Focal segmental glomerulosclerosis cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 t gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-252307 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis ACE receptor protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI down-regulates quantity by destabilization binding 9606 16219810 t The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. SIGNOR-253341 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis benazepril chemical CHEBI:3011 ChEBI ACE receptor protein P12821 UNIPROT down-regulates activity chemical inhibition 9606 16407508 t Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency. SIGNOR-253343 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis AGTR1 receptor protein P30556 UNIPROT NPHS1 protein O60500 UNIPROT down-regulates activity 10116 21982880 f miannu Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism. SIGNOR-253342 0.375 SIGNOR-FSGS Focal segmental glomerulosclerosis AGT extracellular protein P01019 UNIPROT AGTR1 receptor protein P30556 UNIPROT up-regulates activity binding 10116 BTO:0004578 17346243 t AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells) SIGNOR-252293 0.847 SIGNOR-FSGS Focal segmental glomerulosclerosis AGT extracellular protein P01019 UNIPROT TRPC6 receptor protein Q9Y210 UNIPROT up-regulates activity 9606 24850910 f We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels SIGNOR-253331 0.313 SIGNOR-FSGS Focal segmental glomerulosclerosis calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-252320 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis AGTR1 receptor protein P30556 UNIPROT PAX2 factor protein Q02962 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15569307 f Ang II up-regulated Pax-2 gene expression via AT2R in IRPTC (immortalized rat renal proximal tubular cells) SIGNOR-252294 0.26 SIGNOR-FSGS Focal segmental glomerulosclerosis REN extracellular protein P00797 UNIPROT AGT extracellular protein P01019 UNIPROT up-regulates activity cleavage 9606 16816138 t Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I SIGNOR-252297 0.927 SIGNOR-FSGS Focal segmental glomerulosclerosis PLAUR extracellular protein Q03405 UNIPROT ITGB3 receptor protein P05106 UNIPROT up-regulates activity binding 9606 27383564 t Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria SIGNOR-253333 0.445 SIGNOR-FSGS Focal segmental glomerulosclerosis AGT extracellular protein P01019 UNIPROT AGTR1 receptor protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145677 0.847 SIGNOR-FSGS Focal segmental glomerulosclerosis TRPC6 receptor protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 12032305 t Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx SIGNOR-253339 0.8 SIGNOR-FSGS Focal segmental glomerulosclerosis PAXIP1 protein Q6ZW49 UNIPROT PAX2 factor protein Q02962 UNIPROT up-regulates activity binding 10090 BTO:0000944 10908331 t miannu PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein. SIGNOR-236965 0.594 SIGNOR-G Glycogenesis glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267955 0.8 SIGNOR-G Glycogenesis alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267924 0.8 SIGNOR-G Glycogenesis GYS2 protein P54840 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity chemical modification 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-267939 0.2 SIGNOR-G Glycogenesis GYS1 protein P13807 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity chemical modification 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-267940 0.2 SIGNOR-G Glycogenesis UGP2 protein Q16851 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity chemical modification 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267928 0.8 SIGNOR-G Glycogenesis alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267936 0.8 SIGNOR-G Glycogenesis Hexokinase proteinfamily SIGNOR-PF76 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266449 0.8 SIGNOR-G Glycogenesis α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity precursor of 9606 26199317 t miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains SIGNOR-268138 0.8 SIGNOR-G Glycogenesis UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity precursor of 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-268129 0.8 SIGNOR-G Glycogenesis GBE1 protein Q04446 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity chemical modification 9606 26199317 t miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating Œ±-1,6-glucosidic branches from Œ±-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains SIGNOR-267942 0.8 SIGNOR-G Glycogenesis Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-267958 0.7 SIGNOR-G Glycogenesis PYG proteinfamily SIGNOR-PF96 SIGNOR alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267954 0.8 SIGNOR-G Glycogenesis UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR form complex binding 9606 22160681 t miannu Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.  SIGNOR-267923 0.8 SIGNOR-G Glycogenesis Glycogenin proteinfamily SIGNOR-PF95 SIGNOR α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR form complex binding 9606 22160680 t miannu Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.  SIGNOR-267922 0.2 SIGNOR-G Glycogenesis α-D-glucose smallmolecule CHEBI:17925 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266450 0.8 SIGNOR-G Glycogenesis UTP(4-) smallmolecule CHEBI:46398 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267925 0.8 SIGNOR-G Glycogenesis PGM2 protein Q96G03 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267933 0.8 SIGNOR-G Glycogenesis PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267929 0.8 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99729 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000887 18534819 f lperfetto The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-244392 0.468 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner SIGNOR-81395 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74823 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245462 0.885 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Phosphorylation is the signal for ubiquitination lperfetto We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. SIGNOR-106808 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition GFs extracellular stimulus SIGNOR-ST12 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245411 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr SIGNOR-87850 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75629 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 12042314 t lperfetto Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. SIGNOR-244194 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t lperfetto Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir SIGNOR-81442 0.856 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.747 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 SIGNOR-77144 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153479 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 f gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. SIGNOR-69925 0.703 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153483 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.747 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-74835 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245432 0.603 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition E2F1 factor protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 11154267 f lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245468 0.534 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387. SIGNOR-81438 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21524151 t lperfetto P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry. SIGNOR-173425 0.873 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75645 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro. SIGNOR-81407 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251494 0.671 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-75633 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.5 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 t lpetrilli Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation. SIGNOR-160318 0.505 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites SIGNOR-153475 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188408 0.747 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566157 t gcesareni The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry. SIGNOR-29248 0.873 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 17409098 t lperfetto P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). SIGNOR-217505 0.876 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81391 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MYC factor protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102740 0.773 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99725 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81399 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MYC factor protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 f amattioni P27(kip1) gene is a target of transcriptional repression by c-myc. SIGNOR-107032 0.553 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR DNA_replication phenotypesList phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 21524151 f lperfetto In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication SIGNOR-245489 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition RB1 protein P06400 UNIPROT Cell_cycle_block phenotypesList phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-245486 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 f gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes SIGNOR-123087 0.671 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A SIGNOR-245452 0.736 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition E2F1 factor protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8649818 f lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. SIGNOR-245471 0.57 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.747 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 14559997 t Phosphorylation is the signal for ubiquitination gcesareni The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. SIGNOR-118759 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99733 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 8242752 t lperfetto The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. SIGNOR-37145 0.873 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75641 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75637 0.785 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. SIGNOR-107256 0.747 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t lperfetto Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-244202 0.2 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition MYC factor protein P01106 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11154267 t lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245465 0.614 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000007 23429262 t lperfetto We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. SIGNOR-245456 0.638 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.857 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.831 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CDKN2A protein Q8N726 UNIPROT up-regulates activity 9606 25101116 f lperfetto ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. SIGNOR-245493 0.7 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. SIGNOR-250747 0.738 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99721 0.838 SIGNOR-G1-S_trans Cell cycle: G1/S phase transition CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245480 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 t llicata Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions. SIGNOR-55482 0.762 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 15775976 t gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. SIGNOR-134712 0.923 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106432 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition PRKDC protein P78527 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 t gcesareni We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage. SIGNOR-53030 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72060 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245480 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. SIGNOR-251502 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t lperfetto Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-244202 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CDKN2A protein Q8N726 UNIPROT up-regulates activity 9606 25101116 f lperfetto ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. SIGNOR-245493 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81399 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217857 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99725 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t gcesareni Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo SIGNOR-247594 0.762 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 17409098 t lperfetto P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). SIGNOR-217505 0.876 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81391 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Thr1394 SQSDILTtQQRDTMQ 9606 BTO:0002181 11114888 t llicata Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250583 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 t gcesareni Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance SIGNOR-247599 0.762 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000007 23429262 t lperfetto We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. SIGNOR-245456 0.638 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR up-regulates activity binding 10426999 t lperfetto BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex. SIGNOR-251501 0.765 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MYC factor protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102740 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser76 SNLQRMGsSESTDSG 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163150 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72064 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163106 0.841 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition RAD52 protein P43351 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. SIGNOR-251507 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.5 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 8242752 t lperfetto The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. SIGNOR-37145 0.873 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinB/CDK1 complex SIGNOR-C17 SIGNOR G2/M_transition phenotypesList phenotype SIGNOR-PH52 SIGNOR up-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251497 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250581 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN1A protein P38936 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates activity binding 10913154 t lperfetto P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161 SIGNOR-251498 0.848 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-75633 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9168117 t acerquone Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag SIGNOR-48822 0.734 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 t lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. SIGNOR-48818 0.734 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo, SIGNOR-72079 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 16908529 t gcesareni Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase. SIGNOR-148722 0.319 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition BRCA1 protein P38398 UNIPROT Cell_cycle_block phenotypesList phenotype SIGNOR-PH10 SIGNOR up-regulates 15549093 f lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination SIGNOR-251499 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21524151 t lperfetto P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry. SIGNOR-173425 0.873 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72056 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr507 KFRTKSRtWAGEKSK 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163154 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217791 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 t gcesareni Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-91482 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 t lpetrilli Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation. SIGNOR-160318 0.505 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99733 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 14559997 t Phosphorylation is the signal for ubiquitination gcesareni The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. SIGNOR-118759 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser279 VLKRPERsQEESPPG 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163142 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 15775976 t gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. SIGNOR-134716 0.923 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 f gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes SIGNOR-123087 0.671 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75645 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. SIGNOR-151441 0.686 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation 9606 10212258 t gcesareni C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair SIGNOR-67069 0.762 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. SIGNOR-107256 0.747 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition E2F1 factor protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8649818 f lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. SIGNOR-245471 0.57 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.747 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 t lperfetto Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. SIGNOR-72052 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A SIGNOR-245452 0.736 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-87845 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR Mitotic_checkpoint phenotypesList phenotype SIGNOR-PH28 SIGNOR up-regulates 17713585 f lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. SIGNOR-251503 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75637 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99721 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment SIGNOR-150870 0.731 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217799 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315 SIGNOR-251434 0.762 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition HIPK2 protein Q9H2X6 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17210684 t llicata Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation. SIGNOR-151930 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75641 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106436 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition SMAD3 protein P84022 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251494 0.671 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites SIGNOR-153475 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells. SIGNOR-201050 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro. SIGNOR-81407 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188408 0.747 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. SIGNOR-250747 0.738 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566157 t gcesareni The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry. SIGNOR-29248 0.873 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 t lperfetto We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint SIGNOR-177276 0.481 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163110 0.841 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250582 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217803 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). SIGNOR-163146 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition RB1 protein P06400 UNIPROT Cell_cycle_block phenotypesList phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-245486 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR DNA_replication phenotypesList phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 21524151 f lperfetto In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication SIGNOR-245489 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser178 LFTQRQNsAPARMLS 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); SIGNOR-163138 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.747 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition GFs extracellular stimulus SIGNOR-ST12 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245411 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153479 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72072 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 f gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. SIGNOR-69925 0.703 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner SIGNOR-81395 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74823 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks SIGNOR-72048 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245462 0.885 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition E2F1 factor protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 11154267 f lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245468 0.534 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Thr387 HKKLMFKtEGPDSD 9606 BTO:0001321 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217861 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75629 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217795 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Phosphorylation is the signal for ubiquitination lperfetto We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. SIGNOR-106808 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.747 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t lperfetto Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir SIGNOR-81442 0.856 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187591 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser124 PALKRSHsDSLDHDI 9606 20068082 t gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). SIGNOR-163134 0.853 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245432 0.603 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition BUB1 protein O43683 UNIPROT Mitotic_checkpoint phenotypesList phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168192 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition RAD51 protein Q06609 UNIPROT DNA_repair phenotypesList phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 f lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells SIGNOR-251508 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 t Manara The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage SIGNOR-260936 0.413 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153483 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinB/CDK1 complex SIGNOR-C17 SIGNOR Mitotic_checkpoint phenotypesList phenotype SIGNOR-PH28 SIGNOR down-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251496 0.7 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387. SIGNOR-81438 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t gcesareni We show here that c-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. Importantly, the very same site of Rad52 is phosphorylated on exposure of cells to ionizing radiation (IR). SIGNOR-247661 0.671 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR. SIGNOR-251435 0.671 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 t gcesareni We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr SIGNOR-87850 0.831 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 12042314 t lperfetto Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. SIGNOR-244194 0.2 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. SIGNOR-106440 0.791 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK1 protein O14757 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-217853 0.773 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.857 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 SIGNOR-77144 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99729 0.838 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72068 0.813 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000887 18534819 f lperfetto The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-244392 0.468 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-74835 0.785 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 12411508 t lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. SIGNOR-216761 0.842 SIGNOR-G2-M_trans Cell cycle: G2/M phase transition ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-72075 0.813 SIGNOR-GBM Glioblastoma Multiforme mTORC1 complex SIGNOR-C3 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 18372248 t lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. SIGNOR-235518 0.83 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236777 0.2 SIGNOR-GBM Glioblastoma Multiforme BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-GBM Glioblastoma Multiforme PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-GBM Glioblastoma Multiforme MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-244877 0.611 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 12509763 t lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers. SIGNOR-253214 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.72 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-GBM Glioblastoma Multiforme HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236764 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236487 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236531 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252082 0.2 SIGNOR-GBM Glioblastoma Multiforme mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 0.7 SIGNOR-GBM Glioblastoma Multiforme NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000938 24431436 t miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204357 0.807 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 t lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 SIGNOR-236789 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 SIGNOR-GBM Glioblastoma Multiforme PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 SIGNOR-GBM Glioblastoma Multiforme CBL protein P22681 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 t lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. SIGNOR-65642 0.88 SIGNOR-GBM Glioblastoma Multiforme CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236483 0.2 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 SIGNOR-GBM Glioblastoma Multiforme GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-GBM Glioblastoma Multiforme BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-GBM Glioblastoma Multiforme ELK1 factor protein P19419 UNIPROT Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions SIGNOR-233471 0.7 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-GBM Glioblastoma Multiforme GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 t GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. SIGNOR-114704 0.9 SIGNOR-GBM Glioblastoma Multiforme EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates binding 9606 12648462 t lperfetto The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen SIGNOR-22716 0.949 SIGNOR-GBM Glioblastoma Multiforme PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-GBM Glioblastoma Multiforme PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242637 0.934 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236479 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236475 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. SIGNOR-251093 0.2 SIGNOR-GBM Glioblastoma Multiforme CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-110060 0.674 SIGNOR-GBM Glioblastoma Multiforme PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-33633 0.799 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233520 0.2 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-GBM Glioblastoma Multiforme BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. SIGNOR-251474 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 SIGNOR-GBM Glioblastoma Multiforme PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated SIGNOR-250077 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236523 0.2 SIGNOR-GBM Glioblastoma Multiforme mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 0.2 SIGNOR-GBM Glioblastoma Multiforme RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 t lperfetto The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved. SIGNOR-68990 0.84 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235951 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236467 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000675 23616010 lperfetto The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun SIGNOR-236767 0.2 SIGNOR-GBM Glioblastoma Multiforme PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 SIGNOR-GBM Glioblastoma Multiforme EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235956 0.2 SIGNOR-GBM Glioblastoma Multiforme BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252086 0.2 SIGNOR-GBM Glioblastoma Multiforme JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites SIGNOR-235738 0.921 SIGNOR-GBM Glioblastoma Multiforme PIK3R1 protein P27986 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity 10116 21798082 f lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-175678 0.8 SIGNOR-GBM Glioblastoma Multiforme KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.907 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 t miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 0.2 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236516 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236527 0.2 SIGNOR-GBM Glioblastoma Multiforme GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-GBM Glioblastoma Multiforme PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-GBM Glioblastoma Multiforme PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-GBM Glioblastoma Multiforme AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-GBM Glioblastoma Multiforme PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-GBM Glioblastoma Multiforme KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-GBM Glioblastoma Multiforme PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SIGNOR-GBM Glioblastoma Multiforme MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-121959 0.799 SIGNOR-GBM Glioblastoma Multiforme RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. SIGNOR-49477 0.84 SIGNOR-GBM Glioblastoma Multiforme ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236471 0.2 SIGNOR-GBM Glioblastoma Multiforme GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-GBM Glioblastoma Multiforme SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-GBM Glioblastoma Multiforme PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-GBM Glioblastoma Multiforme EGFR receptor protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 t Cbl binds directly to Tyr1045 receptors gcesareni Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2 SIGNOR-147826 0.88 SIGNOR-GBM Glioblastoma Multiforme PTEN protein P60484 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. SIGNOR-248543 0.455 SIGNOR-GBM Glioblastoma Multiforme HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-GCR Glucocorticoid receptor Signaling prednisone chemical CHEBI:8382 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 8143061 t asthma gcesareni SIGNOR-251706 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling prednisolone chemical CHEBI:8378 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 8335191 t Crohn's Disease gcesareni SIGNOR-251701 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling prednisolone chemical CHEBI:8378 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 13760840 t gcesareni SIGNOR-251700 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling STAT5A factor protein P42229 UNIPROT NR3C1/STAT5A factor complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44379 0.551 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 f gcesareni Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. SIGNOR-251678 0.604 SIGNOR-GCR Glucocorticoid receptor Signaling JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-GCR Glucocorticoid receptor Signaling prednisolone chemical CHEBI:8378 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 11777359 t rheumatoid arthritis gcesareni SIGNOR-251699 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling prednisone chemical CHEBI:8382 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 3930339 t ulcerative colitis gcesareni SIGNOR-251702 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9590696 t gcesareni Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP. SIGNOR-251682 0.76 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK3 protein P27361 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 BTO:0001130 12163482 t lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-91139 0.273 SIGNOR-GCR Glucocorticoid receptor Signaling dexamethasone chemical CHEBI:41879 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 t diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies SIGNOR-251694 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling prednisone chemical CHEBI:8382 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 4188963 t dermatitis gcesareni SIGNOR-251705 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK14 protein Q16539 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15824134 f Andrea Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation SIGNOR-255745 0.7 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74872 0.372 SIGNOR-GCR Glucocorticoid receptor Signaling betamethasone chemical CHEBI:3077 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 17561562 t dermatitis gcesareni SIGNOR-251686 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling budesonide chemical CHEBI:3207 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 6958488 t nasal polyposys gcesareni SIGNOR-251688 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-201943 0.785 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 f Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. SIGNOR-257599 0.7 SIGNOR-GCR Glucocorticoid receptor Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK3 protein P27361 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 12163482 t lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein SIGNOR-91143 0.273 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK3 protein P27361 UNIPROT NR3C1 factor protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-154409 0.52 SIGNOR-GCR Glucocorticoid receptor Signaling dehydroepiandrosterone chemical CHEBI:28689 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 9489820 t systemic lupus erythematosus gcesareni SIGNOR-251707 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates phosphorylation Ser395 PSVNPSIsPAHGVAR 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74876 0.372 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 f gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. SIGNOR-251677 0.52 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK14 protein Q16539 UNIPROT NR3C1 factor protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 10090 20660302 t We demonstrate here that AMPK differentially modulates glucocorticoid action by phosphorylating the human GR at serine 211 indirectly through the activation of p38 MAPK SIGNOR-255952 0.487 SIGNOR-GCR Glucocorticoid receptor Signaling 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 6749443 t bronchial ashma gcesareni SIGNOR-251696 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT JUN factor protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 t gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins SIGNOR-251679 0.732 SIGNOR-GCR Glucocorticoid receptor Signaling dexamethasone chemical CHEBI:41879 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 t fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling budesonide chemical CHEBI:3207 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 9657565 t allergic rhinitis gcesareni SIGNOR-251689 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling prednisone chemical CHEBI:8382 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 4344326 t Bell's palsy gcesareni SIGNOR-251704 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT NFKB1 factor protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 t gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins SIGNOR-251680 0.579 SIGNOR-GCR Glucocorticoid receptor Signaling dexamethasone chemical CHEBI:41879 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258711 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling budesonide chemical CHEBI:3207 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 t Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. SIGNOR-253053 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT NR3C1 factor protein P04150 UNIPROT down-regulates activity phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 t lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-249428 0.604 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates activity 10090 11742987 f gcesareni GR-mediated inhibition of c-Jun N-terminal kinase (JNK) activity SIGNOR-251676 0.62 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1/STAT5A factor complex SIGNOR-C84 SIGNOR Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-97562 0.7 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK3 protein P27361 UNIPROT JUN factor protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. SIGNOR-91379 0.774 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 10090 11742987 f gcesareni The MAP kinase p38 is also a target for negative regulation by glucocorticoids SIGNOR-251675 0.487 SIGNOR-GCR Glucocorticoid receptor Signaling NCOA1 factor protein Q15788 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 t miannu Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain. SIGNOR-100258 0.415 SIGNOR-GCR Glucocorticoid receptor Signaling prednisone chemical CHEBI:8382 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 t Crohn's Disease gcesareni SIGNOR-251703 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-GCR Glucocorticoid receptor Signaling prednisolone chemical CHEBI:8378 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 8342904 t ashma gcesareni SIGNOR-251698 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling NFKB1 factor protein P19838 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR form complex binding 9606 9450761 t gcesareni Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna SIGNOR-55375 0.694 SIGNOR-GCR Glucocorticoid receptor Signaling cortisone chemical CHEBI:16962 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 14817168 t allergy gcesareni SIGNOR-251691 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling HSP90AA1 protein P07900 UNIPROT NR3C1 factor protein P04150 UNIPROT down-regulates binding 9606 21511880 t gcesareni We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region. SIGNOR-251667 0.723 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-178639 0.483 SIGNOR-GCR Glucocorticoid receptor Signaling 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 9259419 t rheumatoid arthritis gcesareni SIGNOR-251695 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK14 protein Q16539 UNIPROT NR3C1 factor protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 9606 15817653 t llicata We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis. SIGNOR-135198 0.487 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT NCOA1 factor protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 10660621 t lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. SIGNOR-74880 0.372 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK3 protein P27361 UNIPROT JUN factor protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 t gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. SIGNOR-91383 0.774 SIGNOR-GCR Glucocorticoid receptor Signaling NR3C1 factor protein P04150 UNIPROT HNF4A factor protein P41235 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17978169 t gcesareni Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site. SIGNOR-251684 0.378 SIGNOR-GCR Glucocorticoid receptor Signaling 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 1159081 t inflammation gcesareni SIGNOR-251697 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-GCR Glucocorticoid receptor Signaling budesonide chemical CHEBI:3207 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 11208622 t ashma gcesareni SIGNOR-251687 0.8 SIGNOR-GCR Glucocorticoid receptor Signaling MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-114771 0.483 SIGNOR-GCR Glucocorticoid receptor Signaling budesonide chemical CHEBI:3207 ChEBI NR3C1 factor protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 t Crohn's Disease gcesareni SIGNOR-251690 0.8 SIGNOR-Glycogenolysis Glycogenolysis Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-267958 0.7 SIGNOR-Glycogenolysis Glycogenolysis PHKG2 protein P15735 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 t miannu It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267962 0.649 SIGNOR-Glycogenolysis Glycogenolysis PHKA2 protein P46019 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267406 0.913 SIGNOR-Glycogenolysis Glycogenolysis PHKA2 protein P46019 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267404 0.69 SIGNOR-Glycogenolysis Glycogenolysis PHKA1 protein P46020 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267405 0.679 SIGNOR-Glycogenolysis Glycogenolysis PHKG1 protein Q16816 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267960 0.67 SIGNOR-Glycogenolysis Glycogenolysis PYG proteinfamily SIGNOR-PF96 SIGNOR alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267954 0.8 SIGNOR-Glycogenolysis Glycogenolysis PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267934 0.8 SIGNOR-Glycogenolysis Glycogenolysis α-D-glucose smallmolecule CHEBI:17925 ChEBI Glycolysis phenotypesList phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 23680095 t miannu Glycolysis is a cytoplasmic non-oxidative reaction for glucose degradation that is composed of 9 pro cesses. A non-specific HK enzyme by using ATP phosphorylates glucose following entrance to the cell and converts it to G6P. SIGNOR-267959 0.7 SIGNOR-Glycogenolysis Glycogenolysis alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266577 0.8 SIGNOR-Glycogenolysis Glycogenolysis alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267935 0.8 SIGNOR-Glycogenolysis Glycogenolysis PHKA1 protein P46020 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267407 0.849 SIGNOR-Glycogenolysis Glycogenolysis PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267408 0.2 SIGNOR-Glycogenolysis Glycogenolysis PP1 proteinfamily SIGNOR-PF54 SIGNOR PYG proteinfamily SIGNOR-PF96 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0002049 22225877 t GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation SIGNOR-267961 0.4 SIGNOR-Glycogenolysis Glycogenolysis PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 t Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267409 0.2 SIGNOR-Glycogenolysis Glycogenolysis PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267930 0.8 SIGNOR-Glycogenolysis Glycogenolysis glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267955 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266466 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis pyruvate smallmolecule CHEBI:15361 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266542 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis Aldolase proteinfamily SIGNOR-PF75 SIGNOR glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266486 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis GAPDHS protein O14556 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266497 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266555 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PGAM proteinfamily SIGNOR-PF78 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266516 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267261 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266493 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR SLC2A3 receptor protein P11169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267451 0.371 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 t inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-267788 0.285 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266557 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis FBP1 protein P09467 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267611 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis AMPK complex SIGNOR-C15 SIGNOR GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 t miannu Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  SIGNOR-267578 0.323 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis GPI protein P06744 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266462 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266496 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PK proteinfamily SIGNOR-PF80 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266540 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PDH complex SIGNOR-C402 SIGNOR acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 29059435 t miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. SIGNOR-266541 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266507 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis SLC2A3 receptor protein P11169 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu The SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose SIGNOR-267459 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11744734 t PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1α. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1α SIGNOR-267388 0.356 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266538 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 30193097 t miannu ¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬† SIGNOR-266587 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis SLC2A1 receptor protein P11166 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 t miannu GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. SIGNOR-267458 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis citrate(3-) smallmolecule CHEBI:16947 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity binding 9606 31751601 t miannu Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK. SIGNOR-267579 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis TP53 factor protein P04637 UNIPROT SLC2A4 receptor protein P14672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267465 0.347 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266478 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266577 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis pyruvate smallmolecule CHEBI:15361 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates activity 9606 18613815 f Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. SIGNOR-267384 0.7 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis SLC2A4 receptor protein P14672 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 17403369 t Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis SIGNOR-267291 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PFK proteinfamily SIGNOR-PF79 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266474 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266501 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267456 0.642 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 t gcesareni We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism. SIGNOR-137241 0.2 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267262 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis TP53 factor protein P04637 UNIPROT SLC2A1 receptor protein P11166 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267464 0.586 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267588 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266523 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis pyruvate smallmolecule CHEBI:15361 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266553 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis G6P proteinfamily SIGNOR-PF81 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266567 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PDK1 protein Q15118 UNIPROT PDH complex SIGNOR-C402 SIGNOR down-regulates activity phosphorylation 9606 BTO:0003291 16517405 t miannu PDK1 is a direct HIF-1 target gene. We found that the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) is a direct target of HIF-1. PDK1 phosphorylates the pyruvate dehydrogenase (PDH) E1α subunit and inactivates the PDH enzyme complex that converts pyruvate to acetyl-coenzyme A, thereby inhibiting pyruvate metabolism via the tricarboxylic acid (TCA) cycle SIGNOR-267445 0.625 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-268136 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266510 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis Aldolase proteinfamily SIGNOR-PF75 SIGNOR D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266482 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PC protein P11498 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266552 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis Hexokinase proteinfamily SIGNOR-PF76 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266449 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR SLC2A1 receptor protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267450 0.428 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis SLC25A1 receptor protein P53007 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity relocalization 9606 29651165 t SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate SIGNOR-267289 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis TPI1 protein P60174 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-266492 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotypesList phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 f Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo SIGNOR-267383 0.7 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis α-D-glucose smallmolecule CHEBI:17925 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266450 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis LDHA protein P00338 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 t Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-266919 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity precursor of 9606 24929216 t Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-266920 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 t lperfetto Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. SIGNOR-216639 0.375 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267500 0.365 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266460 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 30193097 t miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† SIGNOR-266586 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis HIF-1 complex factor complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16517405 t miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. SIGNOR-267446 0.424 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis Enolase proteinfamily SIGNOR-PF74 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266527 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis GAPDH protein P04406 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266494 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis PFKFB3 protein Q16875 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267260 0.8 SIGNOR-Glycolysis Glycolysis and Gluconeogenesis beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268073 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266906 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266907 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267530 0.8 SIGNOR-GP Glutamine metabolism GFPT1 protein Q06210 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267818 0.8 SIGNOR-GP Glutamine metabolism GOT2 protein P00505 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267518 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267814 0.8 SIGNOR-GP Glutamine metabolism ASNS protein P08243 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267535 0.8 SIGNOR-GP Glutamine metabolism GOT1 protein P17174 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267510 0.8 SIGNOR-GP Glutamine metabolism GLS2 protein Q9UI32 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266911 0.8 SIGNOR-GP Glutamine metabolism RPS6K proteinfamily SIGNOR-PF26 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0000007 23429703 t Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. SIGNOR-267197 0.2 SIGNOR-GP Glutamine metabolism CAD protein P27708 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 f The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis SIGNOR-267196 0.7 SIGNOR-GP Glutamine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267822 0.8 SIGNOR-GP Glutamine metabolism GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 t Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. SIGNOR-266922 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267191 0.8 SIGNOR-GP Glutamine metabolism SLC1A5 receptor protein Q15758 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266914 0.8 SIGNOR-GP Glutamine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266915 0.8 SIGNOR-GP Glutamine metabolism SLC38A2 receptor protein Q96QD8 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266913 0.8 SIGNOR-GP Glutamine metabolism GMPS protein P49915 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267341 0.8 SIGNOR-GP Glutamine metabolism CPS1 protein P31327 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 f CPSase catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and, as discussed below, controls the flux through the pathway SIGNOR-267195 0.7 SIGNOR-GP Glutamine metabolism GLS protein O94925 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266910 0.8 SIGNOR-GP Glutamine metabolism PPAT protein Q06203 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates activity 9606 28029518 f The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting. SIGNOR-267188 0.7 SIGNOR-GP Glutamine metabolism GLUD1 protein P00367 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 t Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266916 0.8 SIGNOR-GP Glutamine metabolism GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267505 0.8 SIGNOR-GP Glutamine metabolism GLUL protein P15104 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity chemical modification 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267826 0.8 SIGNOR-GP Glutamine metabolism SLC38A1 receptor protein Q9H2H9 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 t Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. SIGNOR-266912 0.8 SIGNOR-GP Glutamine metabolism CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 24332717 t In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities SIGNOR-267194 0.8 SIGNOR-GP Glutamine metabolism L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 11863375 t miannu Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266924 0.8 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267189 0.8 SIGNOR-GP Glutamine metabolism PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed‚Äù SIGNOR-267190 0.8 SIGNOR-GP Glutamine metabolism CPS1 protein P31327 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267192 0.8 SIGNOR-GP Glutamine metabolism PPAT protein Q06203 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267187 0.8 SIGNOR-GP Glutamine metabolism 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 f miannu A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. SIGNOR-267821 0.7 SIGNOR-GP Glutamine metabolism GPT2 protein Q8TD30 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 11863375 t Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 SIGNOR-266925 0.8 SIGNOR-GP Glutamine metabolism ammonium smallmolecule CHEBI:28938 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267823 0.8 SIGNOR-GP Glutamine metabolism PPAT protein Q06203 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267294 0.8 SIGNOR-GP Glutamine metabolism SIRT4 protein Q9Y6E7 UNIPROT GLUD1 protein P00367 UNIPROT down-regulates activity glycosylation 9606 16959573 t miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. SIGNOR-267828 0.601 SIGNOR-GP Glutamine metabolism L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267339 0.8 SIGNOR-GS Glutamatergic synapse DLG4 protein P78352 UNIPROT Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 17243894 f miannu PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD SIGNOR-264230 0.7 SIGNOR-GS Glutamatergic synapse PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 SIGNOR-GS Glutamatergic synapse AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264941 0.8 SIGNOR-GS Glutamatergic synapse PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264960 0.7 SIGNOR-GS Glutamatergic synapse DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 f miannu Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity. SIGNOR-264053 0.7 SIGNOR-GS Glutamatergic synapse SYNGAP1 protein Q96PV0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 t miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. SIGNOR-264229 0.621 SIGNOR-GS Glutamatergic synapse MGluR receptor proteinfamily SIGNOR-PF55 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264689 0.2 SIGNOR-GS Glutamatergic synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI KAR receptor proteinfamily SIGNOR-PF57 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264694 0.8 SIGNOR-GS Glutamatergic synapse CAMK2A protein Q9UQM7 UNIPROT ANKS1B protein Q7Z6G8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 27477489 t miannu CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core. SIGNOR-264231 0.26 SIGNOR-GS Glutamatergic synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 SIGNOR-GS Glutamatergic synapse HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264697 0.2 SIGNOR-GS Glutamatergic synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity chemical activation 9606 15919192 t miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264696 0.8 SIGNOR-GS Glutamatergic synapse 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 receptor protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIGNOR-GS Glutamatergic synapse HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264698 0.2 SIGNOR-GS Glutamatergic synapse DLGAP1 protein O14490 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264588 0.2 SIGNOR-GS Glutamatergic synapse CAMK2A protein Q9UQM7 UNIPROT HOMER proteinfamily SIGNOR-PF59 SIGNOR down-regulates activity phosphorylation -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-264699 0.409 SIGNOR-GS Glutamatergic synapse KAR receptor proteinfamily SIGNOR-PF57 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264940 0.8 SIGNOR-GS Glutamatergic synapse DLGAP1 protein O14490 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264209 0.93 SIGNOR-GS Glutamatergic synapse GNAS protein P63092 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 8245028 t MIANNU The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-265066 0.332 SIGNOR-GS Glutamatergic synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity chemical activation 9606 24564659 t miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264692 0.8 SIGNOR-GS Glutamatergic synapse SHANK3 protein Q9BYB0 UNIPROT Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SIGNOR-264607 0.7 SIGNOR-GS Glutamatergic synapse SHANK3 protein Q9BYB0 UNIPROT NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264701 0.2 SIGNOR-GS Glutamatergic synapse CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1073 PPLQRGKsQQLTVSA -1 14970204 t miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII SIGNOR-262687 0.441 SIGNOR-GS Glutamatergic synapse SHANK1 protein Q9Y566 UNIPROT Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 f miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SIGNOR-264605 0.7 SIGNOR-GS Glutamatergic synapse DLGAP1 protein O14490 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264586 0.85 SIGNOR-GS Glutamatergic synapse NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264704 0.2 SIGNOR-GS Glutamatergic synapse PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264961 0.7 SIGNOR-GS Glutamatergic synapse ACTN1 protein P12814 UNIPROT Actin_cytoskeleton_reorganization phenotypesList phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 17243894 f miannu On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines. SIGNOR-264618 0.7 SIGNOR-GS Glutamatergic synapse NMDA receptor proteinfamily SIGNOR-PF56 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). In contrast, group I mGluRs increase the intracellular Ca2+ concentration via a classical Gq-mediated mechanism that triggers release from intracellular stores through IP3 receptors SIGNOR-264931 0.8 SIGNOR-GS Glutamatergic synapse GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.611 SIGNOR-GS Glutamatergic synapse SHANK3 protein Q9BYB0 UNIPROT AMPA receptor proteinfamily SIGNOR-PF58 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264700 0.2 SIGNOR-GS Glutamatergic synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 SIGNOR-GS Glutamatergic synapse ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-GS Glutamatergic synapse SHANK3 protein Q9BYB0 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264585 0.2 SIGNOR-GS Glutamatergic synapse DLG4 protein P78352 UNIPROT DLGAP1 protein O14490 UNIPROT up-regulates activity relocalization 9606 18923512 t brain lperfetto Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). SIGNOR-264196 0.93 SIGNOR-GS Glutamatergic synapse ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-GS Glutamatergic synapse ANKS1B protein Q7Z6G8 UNIPROT Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 26356309 f miannu AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex. SIGNOR-264226 0.7 SIGNOR-GS Glutamatergic synapse ANKS1B protein Q7Z6G8 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 t miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. SIGNOR-264228 0.466 SIGNOR-GS Glutamatergic synapse 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-GS Glutamatergic synapse glutamic acid extracellular smallmolecule CHEBI:18237 ChEBI MGluR receptor proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264688 0.8 SIGNOR-GS Glutamatergic synapse NLGN1 receptor protein Q8N2Q7 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264191 0.768 SIGNOR-GS Glutamatergic synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 t It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255491 0.8 SIGNOR-GSP GABAergic synapse GPHN protein Q9NQX3 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264975 0.7 SIGNOR-GSP GABAergic synapse CREB1 factor protein P16220 UNIPROT BDNF extracellular protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 t miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. SIGNOR-265062 0.512 SIGNOR-GSP GABAergic synapse ARHGEF9 protein O43307 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264976 0.7 SIGNOR-GSP GABAergic synapse GPHN protein Q9NQX3 UNIPROT GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0000938 21994384 t miannu we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition. SIGNOR-264964 0.2 SIGNOR-GSP GABAergic synapse AP-2 complex complex SIGNOR-C245 SIGNOR GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR down-regulates quantity relocalization 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264990 0.2 SIGNOR-GSP GABAergic synapse ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-GSP GABAergic synapse GABA-B receptor receptor complex SIGNOR-C336 SIGNOR GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-265064 0.454 SIGNOR-GSP GABAergic synapse BDNF extracellular protein P23560 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain SIGNOR-265063 0.7 SIGNOR-GSP GABAergic synapse 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-GSP GABAergic synapse GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264988 0.8 SIGNOR-GSP GABAergic synapse glycine extracellular smallmolecule CHEBI:15428 ChEBI GlyR receptor proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264985 0.8 SIGNOR-GSP GABAergic synapse gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264963 0.8 SIGNOR-GSP GABAergic synapse GABARAP receptor protein O95166 UNIPROT GPHN protein Q9NQX3 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms. SIGNOR-264971 0.584 SIGNOR-GSP GABAergic synapse calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 SIGNOR-GSP GABAergic synapse PKA proteinfamily SIGNOR-PF17 SIGNOR GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity phosphorylation 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264991 0.2 SIGNOR-GSP GABAergic synapse PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 SIGNOR-GSP GABAergic synapse GlyR receptor proteinfamily SIGNOR-PF62 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264984 0.8 SIGNOR-GSP GABAergic synapse GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT up-regulates activity binding 9606 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264973 0.632 SIGNOR-GSP GABAergic synapse GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264996 0.426 SIGNOR-GSP GABAergic synapse GABA-B receptor receptor complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR up-regulates activity binding 9606 BTO:0000938 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265068 0.381 SIGNOR-GSP GABAergic synapse NLGN2 receptor protein Q8NFZ4 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264977 0.7 SIGNOR-GSP GABAergic synapse CACNA1B receptor protein Q00975 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265069 0.8 SIGNOR-GSP GABAergic synapse SLC12A5 receptor protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates activity relocalization 9606 26951057 t miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. SIGNOR-264987 0.8 SIGNOR-GSP GABAergic synapse GPHN protein Q9NQX3 UNIPROT NLGN2 receptor protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264974 0.495 SIGNOR-GSP GABAergic synapse GABARAP receptor protein O95166 UNIPROT GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity binding 9606 BTO:0000938 25882190 t miannu GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors. SIGNOR-264972 0.2 SIGNOR-GSP GABAergic synapse gamma-aminobutyric acid extracellular smallmolecule CHEBI:16865 ChEBI GABA-B receptor receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 18790874 t miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264962 0.8 SIGNOR-GSP GABAergic synapse GNB/GNG complex SIGNOR-C202 SIGNOR CACNA1B receptor protein Q00975 UNIPROT down-regulates activity binding 9606 BTO:0000938 20655485 t miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. SIGNOR-265067 0.396 SIGNOR-GSP GABAergic synapse SLC12A2 receptor protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 26951057 t miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. SIGNOR-264986 0.8 SIGNOR-GSP GABAergic synapse chloride smallmolecule CHEBI:17996 ChEBI Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264989 0.7 SIGNOR-HC Hippo in cancer TEAD proteinfamily SIGNOR-PF22 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230722 0.2 SIGNOR-HC Hippo in cancer LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256187 0.2 SIGNOR-HC Hippo in cancer LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256188 0.2 SIGNOR-HC Hippo in cancer YAP1 factor protein P46937 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199214 0.7 SIGNOR-HC Hippo in cancer STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-256185 0.895 SIGNOR-HC Hippo in cancer WWTR1 factor protein Q9GZV5 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199211 0.7 SIGNOR-HC Hippo in cancer WWTR1 factor protein Q9GZV5 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 SIGNOR-HC Hippo in cancer YAP1 factor protein P46937 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199217 0.7 SIGNOR-HC Hippo in cancer TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2. SIGNOR-256182 0.378 SIGNOR-HC Hippo in cancer Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 21084559 t miannu Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-256186 0.941 SIGNOR-HC Hippo in cancer TEAD proteinfamily SIGNOR-PF22 SIGNOR YAP1 factor protein P46937 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230719 0.2 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser877 CFSSRRSsEASQAEG 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75351 0.44 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser980 VHAPRRCsDGGAHGY 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75359 0.44 SIGNOR-Hedgehog Sonic Hedgehog HHIP extracellular protein Q96QV1 UNIPROT SHH extracellular protein Q15465 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65078 0.893 SIGNOR-Hedgehog Sonic Hedgehog ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 t milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 0.8 SIGNOR-Hedgehog Sonic Hedgehog GLI3 factor protein P10071 UNIPROT PTCH1 receptor protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209641 0.699 SIGNOR-Hedgehog Sonic Hedgehog GLI3 factor protein P10071 UNIPROT PTCH1 receptor protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17419683 f lperfetto Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors. SIGNOR-154240 0.699 SIGNOR-Hedgehog Sonic Hedgehog ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-Hedgehog Sonic Hedgehog KIF7 protein Q2M1P5 UNIPROT GLI3 factor protein P10071 UNIPROT up-regulates quantity by stabilization binding 10090 19592253 t lperfetto These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh. SIGNOR-209614 0.558 SIGNOR-Hedgehog Sonic Hedgehog 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 t milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 0.8 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser865 YLSSRRSsGISPCFS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75347 0.44 SIGNOR-Hedgehog Sonic Hedgehog PTCH1 receptor protein Q13635 UNIPROT SMO receptor protein Q99835 UNIPROT down-regulates activity binding 9606 14556242 t lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. SIGNOR-118609 0.779 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser849 NMLNRRDsSASTISS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75343 0.44 SIGNOR-Hedgehog Sonic Hedgehog GLI1 factor protein P08151 UNIPROT PTCH1 receptor protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin SIGNOR-188875 0.711 SIGNOR-Hedgehog Sonic Hedgehog GLI2 factor protein P10070 UNIPROT GLI1 factor protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209629 0.43 SIGNOR-Hedgehog Sonic Hedgehog GLI1 factor protein P08151 UNIPROT PTCH1 receptor protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209620 0.711 SIGNOR-Hedgehog Sonic Hedgehog SUFU protein Q9UMX1 UNIPROT GLI2 factor protein P10070 UNIPROT down-regulates activity relocalization 10090 16316410 t lperfetto We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms SIGNOR-129065 0.907 SIGNOR-Hedgehog Sonic Hedgehog GLI2 factor protein P10070 UNIPROT PTCH1 receptor protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209632 0.705 SIGNOR-Hedgehog Sonic Hedgehog SMO receptor protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 10090 BTO:0002572 16885213 t lperfetto Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families. SIGNOR-148490 0.397 SIGNOR-Hedgehog Sonic Hedgehog DISP1 protein Q96F81 UNIPROT SHH extracellular protein Q15465 UNIPROT up-regulates activity binding 9606 BTO:0000007 22902404 t lperfetto We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion SIGNOR-191888 0.718 SIGNOR-Hedgehog Sonic Hedgehog SMO receptor protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 23074268 t lperfetto it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity. SIGNOR-199162 0.397 SIGNOR-Hedgehog Sonic Hedgehog GSK3B protein P49841 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 16885213 t lperfetto Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed SIGNOR-148475 0.514 SIGNOR-Hedgehog Sonic Hedgehog SUFU protein Q9UMX1 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates relocalization 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t gcesareni Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol. SIGNOR-72308 0.885 SIGNOR-Hedgehog Sonic Hedgehog GLI1 factor protein P08151 UNIPROT Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 f gcesareni The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors. SIGNOR-235196 0.7 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI2 factor protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 t gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-148478 0.44 SIGNOR-Hedgehog Sonic Hedgehog SMO receptor protein Q99835 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates activity binding 9606 BTO:0000452 22114142 t lperfetto In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling. SIGNOR-177656 0.628 SIGNOR-Hedgehog Sonic Hedgehog 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 0.8 SIGNOR-Hedgehog Sonic Hedgehog GLI3 factor protein P10071 UNIPROT GLI1 factor protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression. SIGNOR-209638 0.433 SIGNOR-Hedgehog Sonic Hedgehog IHH extracellular protein Q14623 UNIPROT PTCH1 receptor protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61311 0.833 SIGNOR-Hedgehog Sonic Hedgehog Cyclopamine chemical CHEBI:4021 ChEBI SMO receptor protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191227 0.8 SIGNOR-Hedgehog Sonic Hedgehog GSK3B protein P49841 UNIPROT GLI2 factor protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser832 GISPYFSsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. SIGNOR-249589 0.541 SIGNOR-Hedgehog Sonic Hedgehog KIF7 protein Q2M1P5 UNIPROT GLI1 factor protein P08151 UNIPROT up-regulates quantity by stabilization binding 10090 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209608 0.606 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser1006 GHGVRRAsDPVRTGS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75339 0.44 SIGNOR-Hedgehog Sonic Hedgehog SMO receptor protein Q99835 UNIPROT KIF7 protein Q2M1P5 UNIPROT up-regulates activity relocalization 10090 19666503 t lperfetto Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins. SIGNOR-209605 0.618 SIGNOR-Hedgehog Sonic Hedgehog GLI1 factor protein P08151 UNIPROT HHIP extracellular protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209623 0.619 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI2 factor protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-154273 0.44 SIGNOR-Hedgehog Sonic Hedgehog GLI2 factor protein P10070 UNIPROT HHIP extracellular protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209635 0.571 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser342 LAHDRAPsRKDSLES 9606 21317289 t gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation. SIGNOR-171999 0.438 SIGNOR-Hedgehog Sonic Hedgehog SHH extracellular protein Q15465 UNIPROT PTCH1 receptor protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 t lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. SIGNOR-61552 0.941 SIGNOR-Hedgehog Sonic Hedgehog KIF7 protein Q2M1P5 UNIPROT GLI2 factor protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 19549984 t lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. SIGNOR-209611 0.568 SIGNOR-Hedgehog Sonic Hedgehog SUFU protein Q9UMX1 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates activity relocalization 10090 10433919 t lperfetto Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling SIGNOR-129068 0.885 SIGNOR-Hedgehog Sonic Hedgehog SUFU protein Q9UMX1 UNIPROT GLI1 factor protein P08151 UNIPROT down-regulates activity binding 15367681 t lperfetto Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1 SIGNOR-249591 0.948 SIGNOR-Hedgehog Sonic Hedgehog SHH extracellular protein Q15465 UNIPROT PTCH1 receptor protein Q13635 UNIPROT down-regulates activity binding 9606 15618519 t lperfetto Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. SIGNOR-132675 0.941 SIGNOR-Hedgehog Sonic Hedgehog GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 t Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) SIGNOR-256499 0.574 SIGNOR-Hedgehog Sonic Hedgehog HHIP extracellular protein Q96QV1 UNIPROT IHH extracellular protein Q14623 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65075 0.701 SIGNOR-Hedgehog Sonic Hedgehog PRKACA protein P17612 UNIPROT GLI3 factor protein P10071 UNIPROT down-regulates quantity phosphorylation Ser907 TDASRRSsEASQSDG 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75355 0.44 SIGNOR-HPP Hippo Signaling YAP1 factor protein P46937 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199214 0.7 SIGNOR-HPP Hippo Signaling TEAD proteinfamily SIGNOR-PF22 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230722 0.2 SIGNOR-HPP Hippo Signaling SCF-betaTRCP complex SIGNOR-C5 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 t lperfetto Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ SIGNOR-230750 0.417 SIGNOR-HPP Hippo Signaling STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-256185 0.895 SIGNOR-HPP Hippo Signaling TJP2 receptor protein Q9UDY2 UNIPROT WWTR1 factor protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 t milica In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz. SIGNOR-175931 0.48 SIGNOR-HPP Hippo Signaling TJP2 receptor protein Q9UDY2 UNIPROT YAP1 factor protein P46937 UNIPROT down-regulates binding 9606 23829894 t milica The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ. SIGNOR-230754 0.495 SIGNOR-HPP Hippo Signaling WWTR1 factor protein Q9GZV5 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199211 0.7 SIGNOR-HPP Hippo Signaling WWTR1 factor protein Q9GZV5 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 SIGNOR-HPP Hippo Signaling WWC1 protein Q8IX03 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 BTO:0000007 21233212 t miannu Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. SIGNOR-263659 0.782 SIGNOR-HPP Hippo Signaling LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256188 0.2 SIGNOR-HPP Hippo Signaling 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates binding 9534 BTO:0004055 12535517 t milica One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-97481 0.2 SIGNOR-HPP Hippo Signaling LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256187 0.2 SIGNOR-HPP Hippo Signaling CTNNA1 protein P35221 UNIPROT YAP1 factor protein P46937 UNIPROT down-regulates binding 9606 23431053 t milica The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-201173 0.36 SIGNOR-HPP Hippo Signaling NEDD4L protein Q96PU5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity ubiquitination Lys396 QITEEEAkLLAQKAA 9606 33058421 t miannu Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control. SIGNOR-263662 0.265 SIGNOR-HPP Hippo Signaling 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT down-regulates binding 9606 21084559 t gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. SIGNOR-169716 0.2 SIGNOR-HPP Hippo Signaling Cell-Cell_contact extracellular stimulus SIGNOR-ST13 SIGNOR CDH1 receptor protein P12830 UNIPROT up-regulates 9606 24532814 f milica Adherens junctions and the cadheriBeta-catenin complex have been found to activate the Hippo signaling pathway and inhibit cell growth. Cadherin-mediated stimulation of the Hippo signaling pathway requires cadherin ligation and the formation of a homophilic bond – consistent with a role in cell-cell contact – and works owing to phosphorylation of YAP by Lats and nuclear exclusion of YAP. SIGNOR-230707 0.7 SIGNOR-HPP Hippo Signaling NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 33058421 t miannu The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin. SIGNOR-263663 0.765 SIGNOR-HPP Hippo Signaling YAP1 factor protein P46937 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199217 0.7 SIGNOR-HPP Hippo Signaling SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 BTO:0000007 19212654 t miannu The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45. SIGNOR-263661 0.89 SIGNOR-HPP Hippo Signaling YAP1 factor protein P46937 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21233212 f miannu We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling. SIGNOR-263660 0.376 SIGNOR-HPP Hippo Signaling AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates binding 10090 21145499 t milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. SIGNOR-170364 0.364 SIGNOR-HPP Hippo Signaling Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 21084559 t miannu Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-256186 0.941 SIGNOR-HPP Hippo Signaling CDH1 receptor protein P12830 UNIPROT CTNNA1 protein P35221 UNIPROT up-regulates binding 9606 24336504 t milica Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm. SIGNOR-203468 0.67 SIGNOR-HPP Hippo Signaling TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2. SIGNOR-256182 0.378 SIGNOR-HPP Hippo Signaling AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT down-regulates binding 10090 21145499 t milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. SIGNOR-170361 0.327 SIGNOR-HPP Hippo Signaling TEAD proteinfamily SIGNOR-PF22 SIGNOR YAP1 factor protein P46937 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230719 0.2 SIGNOR-HPP Hippo Signaling SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 t lperfetto This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap. SIGNOR-217187 0.372 SIGNOR-HT Hepatocellular Tumor BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-HT Hepatocellular Tumor CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 SIGNOR-HT Hepatocellular Tumor EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-HT Hepatocellular Tumor AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244361 0.2 SIGNOR-HT Hepatocellular Tumor TCF4 factor protein P15884 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18852287 t Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. SIGNOR-253324 0.385 SIGNOR-HT Hepatocellular Tumor IGF2 extracellular protein P01344 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251495 0.817 SIGNOR-HT Hepatocellular Tumor IGF1R receptor protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-252690 0.685 SIGNOR-HT Hepatocellular Tumor SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.701 SIGNOR-HT Hepatocellular Tumor ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-HT Hepatocellular Tumor DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227911 0.7 SIGNOR-HT Hepatocellular Tumor LPR5/6 receptor complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. miannu These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin. SIGNOR-256177 0.698 SIGNOR-HT Hepatocellular Tumor SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 0.701 SIGNOR-HT Hepatocellular Tumor PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-HT Hepatocellular Tumor NQO1 protein P15559 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000849 20226854 f irozzo More importantly, our results also indicate that NF-kappaB p50 correlates with the expression of NQO1 and mediates its role in the proliferation of melanoma cells. SIGNOR-256264 0.7 SIGNOR-HT Hepatocellular Tumor EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-252672 0.772 SIGNOR-HT Hepatocellular Tumor TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-HT Hepatocellular Tumor MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250290 0.658 SIGNOR-HT Hepatocellular Tumor Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. SIGNOR-255891 0.2 SIGNOR-HT Hepatocellular Tumor TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 0.703 SIGNOR-HT Hepatocellular Tumor PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-HT Hepatocellular Tumor LEF1 factor protein Q9UJU2 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.622 SIGNOR-HT Hepatocellular Tumor SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-HT Hepatocellular Tumor PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-HT Hepatocellular Tumor AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244357 0.2 SIGNOR-HT Hepatocellular Tumor PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-HT Hepatocellular Tumor HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-HT Hepatocellular Tumor TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 0.703 SIGNOR-HT Hepatocellular Tumor NFE2L2 factor protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 f irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. SIGNOR-256279 0.51 SIGNOR-HT Hepatocellular Tumor GSTA1 protein P08263 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 f irozzo Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line. SIGNOR-256296 0.7 SIGNOR-HT Hepatocellular Tumor PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-HT Hepatocellular Tumor TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-HT Hepatocellular Tumor SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256180 0.528 SIGNOR-HT Hepatocellular Tumor NFE2L2 factor protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 f miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. SIGNOR-254644 0.354 SIGNOR-HT Hepatocellular Tumor GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 SIGNOR-HT Hepatocellular Tumor TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.82 SIGNOR-HT Hepatocellular Tumor PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-HT Hepatocellular Tumor KEAP1 protein Q14145 UNIPROT NFE2L2 factor protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2). SIGNOR-205229 0.809 SIGNOR-HT Hepatocellular Tumor TGFA extracellular protein P01135 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.895 SIGNOR-HT Hepatocellular Tumor SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 0.691 SIGNOR-HT Hepatocellular Tumor SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 0.701 SIGNOR-HT Hepatocellular Tumor MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259110 0.7 SIGNOR-HT Hepatocellular Tumor Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 receptor complex SIGNOR-C219 SIGNOR up-regulates activity binding 9606 23209147 t miannu FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles. SIGNOR-256174 0.802 SIGNOR-HT Hepatocellular Tumor CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 SIGNOR-HT Hepatocellular Tumor HGF extracellular protein P14210 UNIPROT MET receptor protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene. SIGNOR-38429 0.927 SIGNOR-HT Hepatocellular Tumor CTNNB1 protein P35222 UNIPROT TCF4 factor protein P15884 UNIPROT up-regulates activity binding 9606 BTO:0000007 11713476 t amattioni beta-catenin interacts with the TCF/Lef family transcription factors. SIGNOR-178042 0.674 SIGNOR-HT Hepatocellular Tumor TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-HT Hepatocellular Tumor CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-HT Hepatocellular Tumor ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-HT Hepatocellular Tumor MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250289 0.658 SIGNOR-HT Hepatocellular Tumor ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-HT Hepatocellular Tumor MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-HT Hepatocellular Tumor TERT protein O14746 UNIPROT Immortality phenotypesList phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers SIGNOR-252292 0.7 SIGNOR-HT Hepatocellular Tumor SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256181 0.628 SIGNOR-HT Hepatocellular Tumor GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-252676 0.486 SIGNOR-HT Hepatocellular Tumor LEF1 factor protein Q9UJU2 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229767 0.7 SIGNOR-HT Hepatocellular Tumor TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-HT Hepatocellular Tumor AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-HT Hepatocellular Tumor TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.82 SIGNOR-HT Hepatocellular Tumor GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-HT Hepatocellular Tumor PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-HT Hepatocellular Tumor TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-HT Hepatocellular Tumor PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-HT Hepatocellular Tumor HMOX1 protein P09601 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 f irozzo Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.] SIGNOR-256295 0.7 SIGNOR-HT Hepatocellular Tumor NQO1 protein P15559 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003934 28599455 f irozzo The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells. SIGNOR-256265 0.7 SIGNOR-HT Hepatocellular Tumor MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250552 0.658 SIGNOR-HT Hepatocellular Tumor NFE2L2 factor protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 t irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). SIGNOR-256276 0.671 SIGNOR-HT Hepatocellular Tumor EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 SIGNOR-HT Hepatocellular Tumor CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-HT Hepatocellular Tumor HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-HT Hepatocellular Tumor TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 0.703 SIGNOR-HT Hepatocellular Tumor Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 t miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 0.834 SIGNOR-HT Hepatocellular Tumor LEF1 factor protein Q9UJU2 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 SIGNOR-HT Hepatocellular Tumor AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-HT Hepatocellular Tumor SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.628 SIGNOR-HT Hepatocellular Tumor PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-HT Hepatocellular Tumor TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-HT Hepatocellular Tumor BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-HT Hepatocellular Tumor PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-HT Hepatocellular Tumor MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-HT Hepatocellular Tumor SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-HT Hepatocellular Tumor MET receptor protein P08581 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 22128289 t irozzo For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. SIGNOR-256261 0.68 SIGNOR-HT Hepatocellular Tumor MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250288 0.658 SIGNOR-HT Hepatocellular Tumor GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 SIGNOR-HT Hepatocellular Tumor GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 SIGNOR-HT Hepatocellular Tumor SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.691 SIGNOR-IIS Innate Immune Response RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-IIS Innate Immune Response NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-IIS Innate Immune Response IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 t lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction SIGNOR-178053 0.622 SIGNOR-IIS Innate Immune Response Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260867 0.7 SIGNOR-IIS Innate Immune Response G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260863 0.468 SIGNOR-IIS Innate Immune Response TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 SIGNOR-IIS Innate Immune Response TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 14530355 t lperfetto Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling SIGNOR-118458 0.812 SIGNOR-IIS Innate Immune Response TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260156 0.9 SIGNOR-IIS Innate Immune Response IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 t lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 0.911 SIGNOR-IIS Innate Immune Response IKBKE protein Q14164 UNIPROT IRF7 factor protein Q92985 UNIPROT up-regulates phosphorylation Ser471 GTQREGVsSLDSSSL 9606 10893229 t gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. SIGNOR-79139 0.674 SIGNOR-IIS Innate Immune Response DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260191 0.33 SIGNOR-IIS Innate Immune Response IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260140 0.809 SIGNOR-IIS Innate Immune Response DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260192 0.271 SIGNOR-IIS Innate Immune Response G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection SIGNOR-260747 0.7 SIGNOR-IIS Innate Immune Response NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-IIS Innate Immune Response TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 25948473 t lperfetto Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively. SIGNOR-110215 0.616 SIGNOR-IIS Innate Immune Response G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260862 0.468 SIGNOR-IIS Innate Immune Response Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260141 0.7 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-IIS Innate Immune Response IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-IIS Innate Immune Response G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 t miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. SIGNOR-260750 0.315 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-IIS Innate Immune Response G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260864 0.7 SIGNOR-IIS Innate Immune Response MAVS protein Q7Z434 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 t miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  SIGNOR-260143 0.794 SIGNOR-IIS Innate Immune Response TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-IIS Innate Immune Response DDX28 protein Q9NUL7 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261229 0.7 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.818 SIGNOR-IIS Innate Immune Response MAVS protein Q7Z434 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260152 0.2 SIGNOR-IIS Innate Immune Response Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260142 0.7 SIGNOR-IIS Innate Immune Response MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260145 0.91 SIGNOR-IIS Innate Immune Response PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 SIGNOR-IIS Innate Immune Response STING1 protein Q86WV6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260153 0.2 SIGNOR-IIS Innate Immune Response DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260139 0.935 SIGNOR-IIS Innate Immune Response DHX30 protein Q7L2E3 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261228 0.7 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.576 SIGNOR-IIS Innate Immune Response TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways SIGNOR-216298 0.2 SIGNOR-IIS Innate Immune Response IRF7 factor protein Q92985 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16612387 f miannu Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-263128 0.2 SIGNOR-IIS Innate Immune Response Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 f miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260190 0.7 SIGNOR-IIS Innate Immune Response MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-217433 0.707 SIGNOR-IIS Innate Immune Response MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260144 0.823 SIGNOR-IIS Innate Immune Response IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-IIS Innate Immune Response DAMPS extracellular stimulus SIGNOR-ST18 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 25644504 t The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) SIGNOR-252096 0.7 SIGNOR-IIS Innate Immune Response MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 0.844 SIGNOR-IIS Innate Immune Response TRAF6 protein Q9Y4K3 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 10075662 t miannu RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK. SIGNOR-253048 0.615 SIGNOR-IIS Innate Immune Response TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-IIS Innate Immune Response MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.721 SIGNOR-IIS Innate Immune Response Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 SIGNOR-IL1R IL1 Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-IL1R IL1 Signaling MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 0.844 SIGNOR-IL1R IL1 Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR IL1RN extracellular protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. SIGNOR-254794 0.341 SIGNOR-IL1R IL1 Signaling IL1R1 receptor protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. SIGNOR-67140 0.944 SIGNOR-IL1R IL1 Signaling IL1B extracellular protein P01584 UNIPROT IL1R1 receptor protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 0.903 SIGNOR-IL1R IL1 Signaling IL1R1 receptor protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 f lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 0.91 SIGNOR-IL1R IL1 Signaling MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 t lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a SIGNOR-217445 0.713 SIGNOR-IL1R IL1 Signaling IL1RN extracellular protein P18510 UNIPROT IL1R1 receptor protein P14778 UNIPROT down-regulates activity binding 9606 2876877 t Gianni Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β SIGNOR-262302 0.893 SIGNOR-IL1R IL1 Signaling IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251329 0.667 SIGNOR-IL1R IL1 Signaling IL1A extracellular protein P01583 UNIPROT IL1R1 receptor protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 t lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 0.759 SIGNOR-IL1R IL1 Signaling IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000801 17337443 t lperfetto Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation. SIGNOR-153458 0.667 SIGNOR-IL1R IL1 Signaling IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. SIGNOR-251328 0.667 SIGNOR-IL1R IL1 Signaling TOLLIP protein Q9H0E2 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251980 0.792 SIGNOR-IL1R IL1 Signaling NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-IL1R IL1 Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9916987 f gcesareni The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop. SIGNOR-64103 0.674 SIGNOR-IL1R IL1 Signaling PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 27248820 t miannu Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. SIGNOR-259395 0.47 SIGNOR-IL1R IL1 Signaling PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates quantity by expression ubiquitination 9606 17997719 t lperfetto These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells. SIGNOR-159055 0.755 SIGNOR-IL1R IL1 Signaling IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 t lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. SIGNOR-44234 0.911 SIGNOR-IL1R IL1 Signaling IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 t lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 0.911 SIGNOR-IL1R IL1 Signaling MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-IL1R IL1 Signaling TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 t lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 0.933 SIGNOR-IL1R IL1 Signaling TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-IL1R IL1 Signaling MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 17548806 t lperfetto St2825 interfered with recruitment of irak1 and irak4 by myd88, causing inhibition of il-1beta-mediated activation of nf-kappab transcriptional activity. SIGNOR-155385 0.945 SIGNOR-IL1R IL1 Signaling TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205458 0.93 SIGNOR-IL1R IL1 Signaling NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-IL1R IL1 Signaling IL1RAP receptor protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251979 0.619 SIGNOR-IL1R IL1 Signaling IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11960013 t lperfetto In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1. SIGNOR-117315 0.667 SIGNOR-IL1R IL1 Signaling IL1R1 receptor protein P14778 UNIPROT IL1RAP receptor protein Q9NPH3 UNIPROT up-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251981 0.713 SIGNOR-IL1R IL1 Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-IL1R IL1 Signaling IL1A extracellular protein P01583 UNIPROT IL1R1 receptor protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0001573 9565970 t lperfetto Il-1ri is responsible for il-1 signaling SIGNOR-56718 0.759 SIGNOR-IL1R IL1 Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-IL1R IL1 Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-IL1R IL1 Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-IL6 IL6 Signaling SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.769 SIGNOR-IL6 IL6 Signaling STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-IL6 IL6 Signaling NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-IL6 IL6 Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236366 0.965 SIGNOR-IL6 IL6 Signaling PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates sumoylation 9606 15138572 t gcesareni Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins. SIGNOR-124723 0.719 SIGNOR-IL6 IL6 Signaling IL6 extracellular protein P05231 UNIPROT IL6R receptor protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 t fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 0.916 SIGNOR-IL6 IL6 Signaling IL6ST receptor protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 0.66 SIGNOR-IL6 IL6 Signaling SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 9566874 t lperfetto Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. SIGNOR-235445 0.782 SIGNOR-IL6 IL6 Signaling SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-IL6 IL6 Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-IL6 IL6 Signaling CTF1 extracellular protein Q16619 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 9030543 t gcesareni In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling SIGNOR-46509 0.608 SIGNOR-IL6 IL6 Signaling SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44866 0.648 SIGNOR-IL6 IL6 Signaling SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 23454976 t miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition SIGNOR-253051 0.721 SIGNOR-IL6 IL6 Signaling IL6R receptor protein P08887 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 23663276 t milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202033 0.736 SIGNOR-IL6 IL6 Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-IL6 IL6 Signaling JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 t lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-236369 0.794 SIGNOR-IL6 IL6 Signaling IL6ST receptor protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 0.66 SIGNOR-IL6 IL6 Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-IL6 IL6 Signaling JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 0.794 SIGNOR-IL6 IL6 Signaling IL6ST receptor protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 t milica Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. SIGNOR-250574 0.352 SIGNOR-IL6 IL6 Signaling IL6 extracellular protein P05231 UNIPROT IL6R receptor protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. SIGNOR-202030 0.916 SIGNOR-IL6 IL6 Signaling CTF1 extracellular protein Q16619 UNIPROT LIFR receptor protein P42702 UNIPROT up-regulates binding 9606 11834704 t gcesareni We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1 SIGNOR-114758 0.72 SIGNOR-IL6 IL6 Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233520 0.2 SIGNOR-IL6 IL6 Signaling SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. SIGNOR-247341 0.782 SIGNOR-IL6 IL6 Signaling IL6ST receptor protein P40189 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 t lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238621 0.2 SIGNOR-IL6 IL6 Signaling IL6 extracellular protein P05231 UNIPROT IL6R receptor protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 0.916 SIGNOR-IL6 IL6 Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-IL6 IL6 Signaling IL6R receptor protein P08887 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 t gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 0.736 SIGNOR-IL6 IL6 Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 SIGNOR-IL6 IL6 Signaling SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44870 0.648 SIGNOR-IL6 IL6 Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-IL6 IL6 Signaling STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11159537 f miannu STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. SIGNOR-253050 0.7 SIGNOR-IL6 IL6 Signaling LIFR receptor protein P42702 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204850 0.583 SIGNOR-IL6 IL6 Signaling IL6ST receptor protein P40189 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 t lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 0.2 SIGNOR-IL6 IL6 Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-IL6 IL6 Signaling SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-235881 0.965 SIGNOR-IL6 IL6 Signaling PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 9388184 t lperfetto PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3. SIGNOR-238648 0.719 SIGNOR-IL6 IL6 Signaling SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 t gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity SIGNOR-85352 0.72 SIGNOR-IL6 IL6 Signaling ELK1 factor protein P19419 UNIPROT Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions SIGNOR-233471 0.7 SIGNOR-IL6 IL6 Signaling SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 t milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. SIGNOR-202042 0.72 SIGNOR-IL6 IL6 Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-Inflammosome Inflammosome Activation TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-Inflammosome Inflammosome Activation PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263124 0.7 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.576 SIGNOR-Inflammosome Inflammosome Activation Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256375 0.797 SIGNOR-Inflammosome Inflammosome Activation IFNAR receptor complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 SIGNOR-Inflammosome Inflammosome Activation EIF2AK2 protein P19525 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263119 0.332 SIGNOR-Inflammosome Inflammosome Activation ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260158 0.493 SIGNOR-Inflammosome Inflammosome Activation PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263125 0.7 SIGNOR-Inflammosome Inflammosome Activation DAMPS extracellular stimulus SIGNOR-ST18 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 25644504 t The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) SIGNOR-252096 0.7 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.818 SIGNOR-Inflammosome Inflammosome Activation EIF2AK2 protein P19525 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263118 0.308 SIGNOR-Inflammosome Inflammosome Activation PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.362 SIGNOR-Inflammosome Inflammosome Activation IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-Inflammosome Inflammosome Activation PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263127 0.7 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-Inflammosome Inflammosome Activation AIM2 inflammasome complex SIGNOR-C222 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256382 0.2 SIGNOR-Inflammosome Inflammosome Activation EIF2AK2 protein P19525 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263121 0.315 SIGNOR-Inflammosome Inflammosome Activation NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Pyroptosis phenotypesList phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-260355 0.7 SIGNOR-Inflammosome Inflammosome Activation MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.721 SIGNOR-Inflammosome Inflammosome Activation Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 SIGNOR-Inflammosome Inflammosome Activation Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR TNF extracellular protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 0.666 SIGNOR-Inflammosome Inflammosome Activation AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-Inflammosome Inflammosome Activation PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-172132 0.418 SIGNOR-Inflammosome Inflammosome Activation NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Pyroptosis phenotypesList phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-260356 0.7 SIGNOR-Inflammosome Inflammosome Activation PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263126 0.7 SIGNOR-Inflammosome Inflammosome Activation TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260156 0.9 SIGNOR-Inflammosome Inflammosome Activation TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 SIGNOR-Inflammosome Inflammosome Activation RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-Inflammosome Inflammosome Activation AIM2 inflammasome complex SIGNOR-C222 SIGNOR Pyroptosis phenotypesList phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263123 0.7 SIGNOR-Inflammosome Inflammosome Activation TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-Inflammosome Inflammosome Activation EIF2AK2 protein P19525 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263120 0.321 SIGNOR-Inflammosome Inflammosome Activation IFNAR receptor complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 SIGNOR-Inflammosome Inflammosome Activation NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256380 0.2 SIGNOR-Inflammosome Inflammosome Activation Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256376 0.797 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255356 0.566 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260329 0.2 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-Inflammosome Inflammosome Activation NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256381 0.2 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-Inflammosome Inflammosome Activation IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-Inflammosome Inflammosome Activation MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-Inflammosome Inflammosome Activation Caspase 1 complex complex SIGNOR-C220 SIGNOR IL18 extracellular protein Q14116 UNIPROT up-regulates activity cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 t lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256377 0.785 SIGNOR-Inflammosome Inflammosome Activation TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-260151 0.2 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-Inflammosome Inflammosome Activation EIF2AK2 protein P19525 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260159 0.7 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-Inflammosome Inflammosome Activation JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260149 0.716 SIGNOR-Inflammosome Inflammosome Activation NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Pyroptosis phenotypesList phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263122 0.7 SIGNOR-Inflammosome Inflammosome Activation IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-Inflammosome Inflammosome Activation NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. SIGNOR-260346 0.7 SIGNOR-Inflammosome Inflammosome Activation Caspase 1 complex complex SIGNOR-C220 SIGNOR GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | SIGNOR-256415 0.635 SIGNOR-Inflammosome Inflammosome Activation TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-Inflammosome Inflammosome Activation GSDMD protein P57764 UNIPROT Pyroptosis phenotypesList phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis SIGNOR-256416 0.7 SIGNOR-Inflammosome Inflammosome Activation TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260148 0.721 SIGNOR-Inflammosome Inflammosome Activation MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 t miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity SIGNOR-260160 0.92 SIGNOR-Inflammosome Inflammosome Activation NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256384 0.2 SIGNOR-Inflammosome Inflammosome Activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-Inflammosome Inflammosome Activation IFNAR receptor complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260146 0.8 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248408 0.774 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251238 0.671 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236667 0.503 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser434 PPPSDAGsPFQSSPL 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-235797 0.503 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 12747827 t lperfetto Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth. SIGNOR-236678 0.754 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs SIGNOR-235745 0.754 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235499 0.774 SIGNOR-INSR Insulin Signaling RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000011 19299511 t lperfetto These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. SIGNOR-235355 0.791 SIGNOR-INSR Insulin Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-INSR Insulin Signaling PDX1 factor protein P52945 UNIPROT INS extracellular protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255541 0.631 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t lperfetto Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-244337 0.2 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT JUN factor protein P05412 UNIPROT down-regulates activity phosphorylation Ser249 LSPIDMEsQERIKAE -1 1846781 t lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. SIGNOR-18684 0.698 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236645 0.503 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT JUN factor protein P05412 UNIPROT down-regulates activity phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-235892 0.698 SIGNOR-INSR Insulin Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-INSR Insulin Signaling SGK1 protein O00141 UNIPROT FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249134 0.787 SIGNOR-INSR Insulin Signaling HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.933 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236649 0.503 SIGNOR-INSR Insulin Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-51216 0.782 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT JUN factor protein P05412 UNIPROT down-regulates activity phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-236717 0.698 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr256 EHNSTTStFCGTPEY -1 10191262 t miannu PDK1 activates SGK in vitro by phosphorylating Thr256. SIGNOR-250275 0.629 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 17510057 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217071 0.75 SIGNOR-INSR Insulin Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.932 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 15809305 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217067 0.75 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248409 0.774 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251240 0.671 SIGNOR-INSR Insulin Signaling JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-INSR Insulin Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin. SIGNOR-127904 0.782 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.911 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 14967450 t lperfetto Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. SIGNOR-244333 0.2 SIGNOR-INSR Insulin Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-INSR Insulin Signaling PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp SIGNOR-250274 0.629 SIGNOR-INSR Insulin Signaling IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000887 14623899 t lperfetto As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation SIGNOR-236618 0.71 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235503 0.774 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217114 0.754 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 15209375 t lperfetto Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-236637 0.629 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT PDX1 factor protein P52945 UNIPROT down-regulates quantity phosphorylation Ser61 LGALEQGsPPDISPY 10090 BTO:0000783;BTO:0002284 16407209 t Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. SIGNOR-255543 0.2 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217110 0.754 SIGNOR-INSR Insulin Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-INSR Insulin Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-148903 0.782 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 12387817 t lperfetto Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism. SIGNOR-236800 0.629 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.911 SIGNOR-INSR Insulin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t lperfetto Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity SIGNOR-244688 0.2 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.911 SIGNOR-INSR Insulin Signaling PIK3CB protein P42338 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 21779497 t lperfetto The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175241 0.8 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.911 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.911 SIGNOR-INSR Insulin Signaling IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000944 11416002 t lperfetto To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1 SIGNOR-235487 0.71 SIGNOR-INSR Insulin Signaling TSC1 protein Q92574 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 t lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). SIGNOR-217910 0.933 SIGNOR-INSR Insulin Signaling EIF4E protein P06730 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-235964 0.754 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249370 0.774 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 t lperfetto Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase SIGNOR-235793 0.671 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10029 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-235748 0.754 SIGNOR-INSR Insulin Signaling SREBF1 factor protein P36956 UNIPROT Lipogenesis phenotypesList phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 f lperfetto In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), SIGNOR-228614 0.7 SIGNOR-INSR Insulin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 factor protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-244754 0.2 SIGNOR-INSR Insulin Signaling HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. SIGNOR-235786 0.933 SIGNOR-INSR Insulin Signaling EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 16107342 t lperfetto Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells SIGNOR-236641 0.44 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-INSR Insulin Signaling IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 t lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. SIGNOR-236614 0.796 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236690 0.754 SIGNOR-INSR Insulin Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.911 SIGNOR-INSR Insulin Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-INSR Insulin Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127912 0.782 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-236702 0.754 SIGNOR-INSR Insulin Signaling RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-232208 0.791 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248410 0.774 SIGNOR-INSR Insulin Signaling FOXO3 factor protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates quantity transcriptional regulation 10090 20371605 t FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1 SIGNOR-259382 0.465 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251239 0.671 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217141 0.754 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236030 0.503 SIGNOR-INSR Insulin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. SIGNOR-244685 0.2 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249368 0.774 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.911 SIGNOR-INSR Insulin Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249369 0.774 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.911 SIGNOR-INSR Insulin Signaling SGK1 protein O00141 UNIPROT FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 11154281 t lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. SIGNOR-236607 0.787 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-INSR Insulin Signaling PTPN1 protein P18031 UNIPROT INSR receptor protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235495 0.774 SIGNOR-INSR Insulin Signaling GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotypesList phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. SIGNOR-235751 0.7 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.911 SIGNOR-INSR Insulin Signaling RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.733 SIGNOR-INSR Insulin Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-INSR Insulin Signaling TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236698 0.754 SIGNOR-INSR Insulin Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-INSR Insulin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217090 0.754 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 BTO:0000007 10191262 t lperfetto This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1 SIGNOR-236796 0.629 SIGNOR-INSR Insulin Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-INSR Insulin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236694 0.754 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217086 0.754 SIGNOR-INSR Insulin Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser653 PSLSRHSsPHQSEDE 11427888 t Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. SIGNOR-251241 0.671 SIGNOR-INSR Insulin Signaling SGK1 protein O00141 UNIPROT FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249133 0.787 SIGNOR-INSR Insulin Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217137 0.754 SIGNOR-IOA Inhibition of Apoptosis TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. SIGNOR-162638 0.575 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11583623 t lperfetto Xiap is an endogenous inhibitor of caspase-7 SIGNOR-110840 0.852 SIGNOR-IOA Inhibition of Apoptosis MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 t lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a SIGNOR-217445 0.713 SIGNOR-IOA Inhibition of Apoptosis FOXO1 factor protein Q12778 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. SIGNOR-209654 0.562 SIGNOR-IOA Inhibition of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133820 0.807 SIGNOR-IOA Inhibition of Apoptosis BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-IOA Inhibition of Apoptosis BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 10090 12242151 t lperfetto We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. SIGNOR-92939 0.823 SIGNOR-IOA Inhibition of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-IOA Inhibition of Apoptosis CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 SIGNOR-IOA Inhibition of Apoptosis FOXO3 factor protein O43524 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217887 0.7 SIGNOR-IOA Inhibition of Apoptosis TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.864 SIGNOR-IOA Inhibition of Apoptosis TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-IOA Inhibition of Apoptosis CREB1 factor protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001009 10753867 f lperfetto Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival. SIGNOR-76558 0.434 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 t lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-209776 0.266 SIGNOR-IOA Inhibition of Apoptosis RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. SIGNOR-78020 0.406 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 SIGNOR-IOA Inhibition of Apoptosis GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 SIGNOR-IOA Inhibition of Apoptosis CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250557 0.2 SIGNOR-IOA Inhibition of Apoptosis CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.617 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 t lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis SIGNOR-56484 0.92 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding -1 12620238 t lperfetto This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity. SIGNOR-98988 0.92 SIGNOR-IOA Inhibition of Apoptosis BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.789 SIGNOR-IOA Inhibition of Apoptosis BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-IOA Inhibition of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 t lperfetto We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. SIGNOR-178676 0.807 SIGNOR-IOA Inhibition of Apoptosis TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.864 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 SIGNOR-IOA Inhibition of Apoptosis RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells SIGNOR-160635 0.406 SIGNOR-IOA Inhibition of Apoptosis NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-IOA Inhibition of Apoptosis CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-126727 0.515 SIGNOR-IOA Inhibition of Apoptosis SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.769 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11447297 t lperfetto Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect. SIGNOR-109243 0.938 SIGNOR-IOA Inhibition of Apoptosis NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-IOA Inhibition of Apoptosis RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. SIGNOR-249045 0.406 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 t amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). SIGNOR-71954 0.938 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11257231 t lperfetto Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase. SIGNOR-105732 0.852 SIGNOR-IOA Inhibition of Apoptosis MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-IOA Inhibition of Apoptosis BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 15084260 t lperfetto Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-216407 0.532 SIGNOR-IOA Inhibition of Apoptosis PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 t amattioni Xiap is an endogenous inhibitor of caspase-3 SIGNOR-110837 0.938 SIGNOR-IOA Inhibition of Apoptosis XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 11242052 t lperfetto A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis SIGNOR-105702 0.92 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 t lperfetto Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-209769 0.532 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-IOA Inhibition of Apoptosis TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 t lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 0.864 SIGNOR-IOA Inhibition of Apoptosis CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 t lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. SIGNOR-51936 0.437 SIGNOR-IOA Inhibition of Apoptosis SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-IOA Inhibition of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-IOA Inhibition of Apoptosis FOXO3 factor protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. SIGNOR-209657 0.763 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-IOA Inhibition of Apoptosis Survival Factors extracellular stimulus SIGNOR-ST8 SIGNOR BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 9346240 f lperfetto Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. SIGNOR-209693 0.7 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 SIGNOR-IOA Inhibition of Apoptosis CASP7 protein P55210 UNIPROT Caspase 7 complex complex SIGNOR-C232 SIGNOR form complex binding cleavage:Asp206 SGPINDTdANPRYKI 11701129 t lperfetto The quaternary structure of caspase-7 comprises two closely associated heterodimers, with each heterodimer consisting of a large and a small subunit. SIGNOR-256394 0.2 SIGNOR-IOA Inhibition of Apoptosis AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-IOA Inhibition of Apoptosis Survival Factors extracellular stimulus SIGNOR-ST8 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity 19282669 f lperfetto Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop. SIGNOR-250559 0.7 SIGNOR-IOA Inhibition of Apoptosis IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 23332762 t lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. SIGNOR-216399 0.266 SIGNOR-IOA Inhibition of Apoptosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 f amattioni Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors SIGNOR-96834 0.7 SIGNOR-IOA Inhibition of Apoptosis CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-IOA Inhibition of Apoptosis CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-IOA Inhibition of Apoptosis MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-IOA Inhibition of Apoptosis NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-IOA Inhibition of Apoptosis CREB1 factor protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis SIGNOR-43927 0.434 SIGNOR-IOA Inhibition of Apoptosis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250558 0.2 SIGNOR-IOA Inhibition of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1 SIGNOR-133823 0.807 SIGNOR-IOA Inhibition of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-IOA Inhibition of Apoptosis GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-IOA Inhibition of Apoptosis BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-IOA Inhibition of Apoptosis CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.617 SIGNOR-IOA Inhibition of Apoptosis RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-180910 0.406 SIGNOR-IOA Inhibition of Apoptosis TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-IOA Inhibition of Apoptosis RPS6KA1 protein Q15418 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-72117 0.738 SIGNOR-IoT Initiation of Translation EIF5B protein O60841 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates activity relocalization 9606 30551605 t lperfetto EIF5B was also shown to deliver Met-tRNAi into the P-site of the ribosome in an eIF2-independent translation initiation mechanism utilized by the CSFV and HCV IRESs  SIGNOR-269119 0.8 SIGNOR-IoT Initiation of Translation EIF2B1 protein Q14232 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269124 0.822 SIGNOR-IoT Initiation of Translation 48S_initiation_complex complex SIGNOR-C454 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates activity binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269169 0.2 SIGNOR-IoT Initiation of Translation EIF1 protein P41567 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 t lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning SIGNOR-269143 0.54 SIGNOR-IoT Initiation of Translation EIF5B protein O60841 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269121 0.602 SIGNOR-IoT Initiation of Translation GTP smallmolecule CHEBI:15996 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269118 0.8 SIGNOR-IoT Initiation of Translation 48S_initiation_complex complex SIGNOR-C454 SIGNOR MRNA_scanning phenotype SIGNOR-PH208 SIGNOR up-regulates 9606 29401259 f lperfetto The 48S complex scans mRNA from 5′ to 3′ until it identifies an AUG start codon in an appropriate sequence context (Kozak consensus) SIGNOR-269168 0.7 SIGNOR-IoT Initiation of Translation EIF5 protein P55010 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269163 0.784 SIGNOR-IoT Initiation of Translation messenger RNA smallmolecule CHEBI:33699 ChEBI 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269164 0.8 SIGNOR-IoT Initiation of Translation EIF2S1 protein P05198 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269114 0.943 SIGNOR-IoT Initiation of Translation 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269171 0.2 SIGNOR-IoT Initiation of Translation EIF5 protein P55010 UNIPROT EIF5B protein O60841 UNIPROT up-regulates activity relocalization 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269122 0.742 SIGNOR-IoT Initiation of Translation EIF4B protein P23588 UNIPROT 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269165 0.2 SIGNOR-IoT Initiation of Translation Met-tRNA(Met) chemical CHEBI:16635 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269117 0.8 SIGNOR-IoT Initiation of Translation EIF1 protein P41567 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269161 0.662 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269154 0.617 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 15703437 f lperfetto EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes SIGNOR-269149 0.402 SIGNOR-IoT Initiation of Translation 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269167 0.2 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR EIF5 protein P55010 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269153 0.684 SIGNOR-IoT Initiation of Translation eIF4F_complex complex SIGNOR-C44 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269166 0.838 SIGNOR-IoT Initiation of Translation EIF5B protein O60841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269120 0.656 SIGNOR-IoT Initiation of Translation 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269173 0.7 SIGNOR-IoT Initiation of Translation EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 14654845 t lperfetto The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Here we show that 60S subunits are activated by release of eIF6 (also termed p27BBP). | Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. SIGNOR-269150 0.504 SIGNOR-IoT Initiation of Translation 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269160 0.2 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269162 0.66 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269158 0.623 SIGNOR-IoT Initiation of Translation 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269170 0.2 SIGNOR-IoT Initiation of Translation Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269159 0.2 SIGNOR-IoT Initiation of Translation EIF3_complex complex SIGNOR-C401 SIGNOR EIF1 protein P41567 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269152 0.606 SIGNOR-IoT Initiation of Translation messenger RNA smallmolecule CHEBI:33699 ChEBI 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269172 0.8 SIGNOR-IoT Initiation of Translation EIF1 protein P41567 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 f lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S SIGNOR-269144 0.264 SIGNOR-IS Integrin Signaling ELK1 factor protein P19419 UNIPROT Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 f lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions SIGNOR-233471 0.7 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT ITGB4 receptor protein P16144 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257689 0.2 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183612 0.2 SIGNOR-IS Integrin Signaling TEAD proteinfamily SIGNOR-PF22 SIGNOR YAP1 factor protein P46937 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230719 0.2 SIGNOR-IS Integrin Signaling Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259004 0.351 SIGNOR-IS Integrin Signaling A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257706 0.558 SIGNOR-IS Integrin Signaling Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257719 0.666 SIGNOR-IS Integrin Signaling FOXO3 factor protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0004245 10783894 t gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. SIGNOR-238610 0.737 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150476 0.629 SIGNOR-IS Integrin Signaling ECM extracellular stimulus SIGNOR-ST20 SIGNOR A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259035 0.7 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 SIGNOR-IS Integrin Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257628 0.455 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257659 0.356 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257690 0.2 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 SIGNOR-IS Integrin Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT ITGB1 receptor protein P05556 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257638 0.762 SIGNOR-IS Integrin Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-IS Integrin Signaling Kindlin proteinfamily SIGNOR-PF48 SIGNOR A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259000 0.445 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252082 0.2 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257626 0.676 SIGNOR-IS Integrin Signaling ITGB4 receptor protein P16144 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257720 0.566 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT ITGB3 receptor protein P05106 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257656 0.313 SIGNOR-IS Integrin Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR ITGB4 receptor protein P16144 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259031 0.2 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 SIGNOR-IS Integrin Signaling FOXO3 factor protein O43524 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217887 0.7 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257639 0.762 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT ITGB3 receptor protein P05106 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257687 0.34 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257688 0.34 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257670 0.32 SIGNOR-IS Integrin Signaling CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245480 0.7 SIGNOR-IS Integrin Signaling RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000975 11018021 t lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244945 0.733 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183620 0.2 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257608 0.678 SIGNOR-IS Integrin Signaling A1/b1 integrin receptor complex SIGNOR-C159 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257701 0.558 SIGNOR-IS Integrin Signaling WWTR1 factor protein Q9GZV5 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150484 0.629 SIGNOR-IS Integrin Signaling PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257731 0.674 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183616 0.2 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT ITGB1 receptor protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257607 0.787 SIGNOR-IS Integrin Signaling ITGB4 receptor protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-252697 0.395 SIGNOR-IS Integrin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation 9606 22085529 t miannu Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. SIGNOR-259029 0.2 SIGNOR-IS Integrin Signaling A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257721 0.493 SIGNOR-IS Integrin Signaling PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 t gcesareni Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events. SIGNOR-106824 0.793 SIGNOR-IS Integrin Signaling A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 9428518 t miannu Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-259033 0.4 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT ITGB4 receptor protein P16144 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257658 0.357 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257613 0.608 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-134212 0.629 SIGNOR-IS Integrin Signaling ECM extracellular stimulus SIGNOR-ST20 SIGNOR A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259034 0.7 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT ITGB3 receptor protein P05106 UNIPROT up-regulates activity binding 10090 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257625 0.782 SIGNOR-IS Integrin Signaling PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257732 0.912 SIGNOR-IS Integrin Signaling Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259001 0.475 SIGNOR-IS Integrin Signaling CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 17409098 t lperfetto P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). SIGNOR-217505 0.876 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252086 0.2 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257644 0.762 SIGNOR-IS Integrin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 SIGNOR-IS Integrin Signaling PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 15688067 t miannu Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade. SIGNOR-257733 0.692 SIGNOR-IS Integrin Signaling TLN1 protein Q9Y490 UNIPROT ITGB4 receptor protein P16144 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257627 0.482 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT ITGB1 receptor protein P05556 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257669 0.32 SIGNOR-IS Integrin Signaling LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 factor protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256188 0.2 SIGNOR-IS Integrin Signaling Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259018 0.413 SIGNOR-IS Integrin Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256166 0.2 SIGNOR-IS Integrin Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR A6/b4 integrin receptor complex SIGNOR-C174 SIGNOR up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259032 0.2 SIGNOR-IS Integrin Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150492 0.629 SIGNOR-IS Integrin Signaling ECM extracellular stimulus SIGNOR-ST20 SIGNOR A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259037 0.7 SIGNOR-IS Integrin Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259030 0.2 SIGNOR-IS Integrin Signaling ITGB1 receptor protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257700 0.696 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150480 0.629 SIGNOR-IS Integrin Signaling SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates activity phosphorylation 9606 30889378 t miannu SRC can directly phosphorylate and inhibit LATS SIGNOR-259056 0.393 SIGNOR-IS Integrin Signaling ITGB1BP1 protein O14713 UNIPROT Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257657 0.283 SIGNOR-IS Integrin Signaling ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. SIGNOR-250261 0.772 SIGNOR-IS Integrin Signaling HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.933 SIGNOR-IS Integrin Signaling TEAD proteinfamily SIGNOR-PF22 SIGNOR WWTR1 factor protein Q9GZV5 UNIPROT up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230722 0.2 SIGNOR-IS Integrin Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-IS Integrin Signaling ITGB3 receptor protein P05106 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257718 0.649 SIGNOR-IS Integrin Signaling HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. SIGNOR-235786 0.933 SIGNOR-IS Integrin Signaling PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-IS Integrin Signaling WWTR1 factor protein Q9GZV5 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199211 0.7 SIGNOR-IS Integrin Signaling DOK1 protein Q99704 UNIPROT A6/b1 integrin receptor complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257675 0.32 SIGNOR-IS Integrin Signaling ECM extracellular stimulus SIGNOR-ST20 SIGNOR Av/b3 integrin receptor complex SIGNOR-C177 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259036 0.7 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.911 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.911 SIGNOR-LBC Luminal Breast Cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 t lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. SIGNOR-244784 0.2 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-LBC Luminal Breast Cancer TSC complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 f lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor SIGNOR-251527 0.615 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-244651 0.2 SIGNOR-LBC Luminal Breast Cancer mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-LBC Luminal Breast Cancer CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-LBC Luminal Breast Cancer PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001271 20596030 f lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166478 0.662 SIGNOR-LBC Luminal Breast Cancer IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 t lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. SIGNOR-236614 0.796 SIGNOR-LBC Luminal Breast Cancer PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-244439 0.662 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-LBC Luminal Breast Cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-LBC Luminal Breast Cancer RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000011 19299511 t lperfetto These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. SIGNOR-235355 0.791 SIGNOR-LBC Luminal Breast Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.911 SIGNOR-LBC Luminal Breast Cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244255 0.2 SIGNOR-LBC Luminal Breast Cancer PIK3CA protein P42336 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation SIGNOR-254353 0.7 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.857 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 SIGNOR-LBC Luminal Breast Cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-LBC Luminal Breast Cancer AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-LBC Luminal Breast Cancer 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 factor protein P03372 UNIPROT up-regulates chemical activation 9606 BTO:0000150 17478088 t gcesareni Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters. SIGNOR-154660 0.8 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-244647 0.2 SIGNOR-LBC Luminal Breast Cancer TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-LBC Luminal Breast Cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-LBC Luminal Breast Cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.857 SIGNOR-LBC Luminal Breast Cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244247 0.2 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-LBC Luminal Breast Cancer CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-244655 0.2 SIGNOR-LBC Luminal Breast Cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.911 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 SIGNOR-LBC Luminal Breast Cancer PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.812 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244858 0.743 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 receptor protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 t lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling SIGNOR-244541 0.2 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-LBC Luminal Breast Cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-LBC Luminal Breast Cancer RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.911 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 SIGNOR-LBC Luminal Breast Cancer KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244251 0.2 SIGNOR-LBC Luminal Breast Cancer BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.641 SIGNOR-LBC Luminal Breast Cancer CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 395188 t lperfetto Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. SIGNOR-251528 0.8 SIGNOR-LBC Luminal Breast Cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.743 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244862 0.743 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.857 SIGNOR-LBC Luminal Breast Cancer PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.812 SIGNOR-LBC Luminal Breast Cancer ESR1 factor protein P03372 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 18247370 t miannu The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells. SIGNOR-263656 0.709 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. SIGNOR-244396 0.73 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 factor protein Q01094 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233526 0.2 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.911 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259919 0.2 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000675 23616010 lperfetto The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun SIGNOR-236767 0.2 SIGNOR-LBC Luminal Breast Cancer RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-LBC Luminal Breast Cancer KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.907 SIGNOR-LBC Luminal Breast Cancer FGF1 extracellular protein P05230 UNIPROT FGFR1 receptor protein P11362 UNIPROT up-regulates binding 9606 11030354 t lperfetto Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization. SIGNOR-83143 0.911 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254952 0.7 SIGNOR-LBC Luminal Breast Cancer INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-LBC Luminal Breast Cancer JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.911 SIGNOR-LBC Luminal Breast Cancer PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-209856 0.724 SIGNOR-LBC Luminal Breast Cancer IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-168985 0.708 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-LBC Luminal Breast Cancer JUN factor protein P05412 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254876 0.353 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 12509763 t lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers. SIGNOR-253214 0.2 SIGNOR-LBC Luminal Breast Cancer FRS2 receptor protein Q8WU20 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236953 0.794 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-LBC Luminal Breast Cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.911 SIGNOR-LBC Luminal Breast Cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-LBC Luminal Breast Cancer RB1 protein P06400 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-262533 0.7 SIGNOR-LBC Luminal Breast Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-LBC Luminal Breast Cancer TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-LBC Luminal Breast Cancer mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-256064 0.7 SIGNOR-LBC Luminal Breast Cancer PIK3CA protein P42336 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 9606 11160134 f lperfetto Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307 SIGNOR-104911 0.708 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-257606 0.7 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.72 SIGNOR-LBC Luminal Breast Cancer TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-LBC Luminal Breast Cancer FGFR1 receptor protein P11362 UNIPROT FRS2 receptor protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236944 0.862 SIGNOR-LBC Luminal Breast Cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-LBC Luminal Breast Cancer RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-232208 0.791 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-LBC Luminal Breast Cancer PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.857 SIGNOR-LBC Luminal Breast Cancer CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 factor protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244243 0.2 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-LBC Luminal Breast Cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-LBC Luminal Breast Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.857 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 SIGNOR-LBC Luminal Breast Cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.911 SIGNOR-LBC Luminal Breast Cancer mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotypesList phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 f lperfetto Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1. SIGNOR-209919 0.7 SIGNOR-LBC Luminal Breast Cancer FGFR1 receptor protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 f lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-244865 0.317 SIGNOR-LBC Luminal Breast Cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 SIGNOR-LBC Luminal Breast Cancer CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.857 SIGNOR-LBC Luminal Breast Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-LBC Luminal Breast Cancer E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-LR Leptin Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-LR Leptin Signaling STAT5A factor protein P42229 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-210146 0.7 SIGNOR-LR Leptin Signaling LEP extracellular protein P41159 UNIPROT LEPR receptor protein P48357 UNIPROT up-regulates binding 9606 9463481 t gcesareni Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response SIGNOR-55656 0.809 SIGNOR-LR Leptin Signaling ACACA protein Q13085 UNIPROT Food intake extracellular phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0003336 25343030 f miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. SIGNOR-263509 0.7 SIGNOR-LR Leptin Signaling AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 f miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. SIGNOR-260096 0.547 SIGNOR-LR Leptin Signaling STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 SIGNOR-LR Leptin Signaling FOXO1 factor protein Q12778 UNIPROT NPY extracellular protein P01303 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263502 0.416 SIGNOR-LR Leptin Signaling FOXO1 factor protein Q12778 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 f Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. SIGNOR-254973 0.7 SIGNOR-LR Leptin Signaling JAK2 protein O60674 UNIPROT LEPR receptor protein P48357 UNIPROT up-regulates activity phosphorylation Tyr986 QRQPFVKyATLISNS 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263493 0.766 SIGNOR-LR Leptin Signaling JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.786 SIGNOR-LR Leptin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† SIGNOR-244311 0.2 SIGNOR-LR Leptin Signaling MC4R receptor protein P32245 UNIPROT Food intake extracellular phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 33094623 f miannu Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. Adipose tissue derived hormone leptin induces negative energy balance by stimulating α-MSH and melanocortin-4 receptor (MC4R) (Friedman 1997, Kask et al. 1998). Increased melanocortin signaling in hypotalamus leads not only to decreased food intake but also increases sympathetic nervous system outflow to skeletal muscle, energy expenditure and physical activity SIGNOR-263504 0.7 SIGNOR-LR Leptin Signaling MTOR protein P42345 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255841 0.557 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0001282 18718905 t miannu Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. SIGNOR-263491 0.766 SIGNOR-LR Leptin Signaling AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-LR Leptin Signaling SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity 9606 24600449 f miannu A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. SIGNOR-255330 0.7 SIGNOR-LR Leptin Signaling STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-LR Leptin Signaling STAT3 protein P40763 UNIPROT POMC extracellular protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 19049975 t miannu We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. SIGNOR-263497 0.625 SIGNOR-LR Leptin Signaling AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 12015362 t lperfetto Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. SIGNOR-216655 0.537 SIGNOR-LR Leptin Signaling FOXO1 factor protein Q12778 UNIPROT POMC extracellular protein P01189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000614 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263503 0.421 SIGNOR-LR Leptin Signaling JAK2 protein O60674 UNIPROT LEPR receptor protein P48357 UNIPROT up-regulates activity phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263494 0.766 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates activity binding 27154742 t lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex SIGNOR-253077 0.344 SIGNOR-LR Leptin Signaling PPARG factor protein P37231 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 0.7 SIGNOR-LR Leptin Signaling EGR1 factor protein P18146 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003336 29212876 t miannu Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC. SIGNOR-263508 0.605 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 9606 11085989 t miannu Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2 SIGNOR-263506 0.486 SIGNOR-LR Leptin Signaling FOXO1 factor protein Q12778 UNIPROT AGRP extracellular protein O00253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263501 0.458 SIGNOR-LR Leptin Signaling NPY extracellular protein P01303 UNIPROT Food intake extracellular phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 10195157 f miannu Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. SIGNOR-263505 0.7 SIGNOR-LR Leptin Signaling FOS factor protein P01100 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR form complex binding -1 3142692 t irozzo The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. SIGNOR-256366 0.951 SIGNOR-LR Leptin Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGR1 factor protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11085989 f miannu We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway.  SIGNOR-263507 0.2 SIGNOR-LR Leptin Signaling RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS factor protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. SIGNOR-252789 0.2 SIGNOR-LR Leptin Signaling RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 t lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. SIGNOR-252787 0.2 SIGNOR-LR Leptin Signaling POMC extracellular protein P01189 UNIPROT MC4R receptor protein P32245 UNIPROT up-regulates activity binding 9606 20694162 t miannu α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R) SIGNOR-252373 0.772 SIGNOR-LR Leptin Signaling SH2B1 protein Q9NRF2 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 27154742 t lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex SIGNOR-253078 0.676 SIGNOR-LR Leptin Signaling FOXO1 factor protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0000007 25510553 t miannu FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. SIGNOR-263496 0.58 SIGNOR-LR Leptin Signaling PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 t We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association SIGNOR-248665 0.786 SIGNOR-LR Leptin Signaling PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 f miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. SIGNOR-263499 0.861 SIGNOR-LR Leptin Signaling PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001282 18718905 t miannu These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2. SIGNOR-263492 0.751 SIGNOR-LR Leptin Signaling AGRP extracellular protein O00253 UNIPROT MC4R receptor protein P32245 UNIPROT down-regulates activity binding 9606 10318826 t miannu AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor. SIGNOR-252379 0.768 SIGNOR-LR Leptin Signaling IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-252695 0.757 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000007 11018044 t miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. SIGNOR-263495 0.751 SIGNOR-LR Leptin Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-LR Leptin Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 SIGNOR-LR Leptin Signaling JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.813 SIGNOR-LR Leptin Signaling STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12565872 t We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells SIGNOR-253583 0.7 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT POMC extracellular protein P01189 UNIPROT up-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253074 0.486 SIGNOR-LR Leptin Signaling LEPR receptor protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 9606 BTO:0003336 25343030 f miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. SIGNOR-263510 0.378 SIGNOR-LR Leptin Signaling JAK2 protein O60674 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 t gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation SIGNOR-56827 0.863 SIGNOR-LR Leptin Signaling PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 10660596 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-74856 0.892 SIGNOR-M1M2 Macrophage polarization MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-M1M2 Macrophage polarization NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  SIGNOR-249519 0.7 SIGNOR-M1M2 Macrophage polarization JAK2 protein O60674 UNIPROT STAT6 factor protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 t gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. SIGNOR-62585 0.659 SIGNOR-M1M2 Macrophage polarization MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 SIGNOR-236376 0.712 SIGNOR-M1M2 Macrophage polarization MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 t lperfetto Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3, SIGNOR-235704 0.591 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19567879 f lperfetto We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. SIGNOR-249539 0.449 SIGNOR-M1M2 Macrophage polarization IRF4 factor protein Q15306 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249559 0.7 SIGNOR-M1M2 Macrophage polarization TLR4 receptor protein O00206 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 BTO:0000801 7635431 f lperfetto The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2). SIGNOR-249517 0.564 SIGNOR-M1M2 Macrophage polarization SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 t lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 0.787 SIGNOR-M1M2 Macrophage polarization RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-M1M2 Macrophage polarization MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-M1M2 Macrophage polarization IL4 extracellular protein P05112 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 t lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 0.941 SIGNOR-M1M2 Macrophage polarization IRF4 factor protein Q15306 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 20729857 f lperfetto We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses. SIGNOR-249543 0.7 SIGNOR-M1M2 Macrophage polarization TLR4 receptor protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 t fstefani Mappit analysis of early toll-like receptor signalling events. SIGNOR-160424 0.722 SIGNOR-M1M2 Macrophage polarization MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-M1M2 Macrophage polarization JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase SIGNOR-236463 0.813 SIGNOR-M1M2 Macrophage polarization MAPK8 protein P45983 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 9030579 t llicata The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions. SIGNOR-46518 0.548 SIGNOR-M1M2 Macrophage polarization IFNG extracellular protein P01579 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 f lperfetto IFN-_ induces socs1 gene expression through an inducible factor SIGNOR-236809 0.537 SIGNOR-M1M2 Macrophage polarization IL10 extracellular protein P22301 UNIPROT IL10RA receptor protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 t lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 0.911 SIGNOR-M1M2 Macrophage polarization IRF4 factor protein Q15306 UNIPROT IL4 extracellular protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 f IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production SIGNOR-254501 0.547 SIGNOR-M1M2 Macrophage polarization STAT3 protein P40763 UNIPROT IL10 extracellular protein P22301 UNIPROT up-regulates transcriptional regulation 9606 28713870 f svumbaca These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression SIGNOR-256234 0.784 SIGNOR-M1M2 Macrophage polarization SOCS1 protein O15524 UNIPROT IFNG extracellular protein P01579 UNIPROT down-regulates 9606 21628332 f lperfetto SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease. SIGNOR-249571 0.537 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249533 0.534 SIGNOR-M1M2 Macrophage polarization KDM6B protein O15054 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249564 0.7 SIGNOR-M1M2 Macrophage polarization M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR IL10 extracellular protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0000801 BTO:0001103 22933625 f apalma P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch SIGNOR-255448 0.7 SIGNOR-M1M2 Macrophage polarization MAPK8 protein P45983 UNIPROT STAT6 factor protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 t llicata Deactivation of stat6 through serine 707 phosphorylation by jnk. SIGNOR-170153 0.366 SIGNOR-M1M2 Macrophage polarization STAT3 protein P40763 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 f lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. SIGNOR-249547 0.7 SIGNOR-M1M2 Macrophage polarization PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLR4 receptor protein O00206 UNIPROT up-regulates activity 9606 BTO:0000801 19946286 f lperfetto The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. SIGNOR-249516 0.7 SIGNOR-M1M2 Macrophage polarization STAT3 protein P40763 UNIPROT IL10 extracellular protein P22301 UNIPROT up-regulates transcriptional regulation 9606 22378047 f IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype SIGNOR-254515 0.784 SIGNOR-M1M2 Macrophage polarization IL4 extracellular protein P05112 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates binding -1 10219247 t gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). SIGNOR-67217 0.941 SIGNOR-M1M2 Macrophage polarization MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17563747 t lperfetto Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. SIGNOR-236346 0.298 SIGNOR-M1M2 Macrophage polarization IRF4 factor protein Q15306 UNIPROT M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249561 0.7 SIGNOR-M1M2 Macrophage polarization PPARG factor protein P37231 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 f lperfetto This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype. SIGNOR-249542 0.7 SIGNOR-M1M2 Macrophage polarization TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 9606 BTO:0000801 14519765 t lperfetto Tram binds trif directly and recruits it to tlr4 SIGNOR-118367 0.564 SIGNOR-M1M2 Macrophage polarization IL4R receptor protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 t lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 0.605 SIGNOR-M1M2 Macrophage polarization MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). SIGNOR-251419 0.736 SIGNOR-M1M2 Macrophage polarization TLR4 receptor protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252067 0.842 SIGNOR-M1M2 Macrophage polarization IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-M1M2 Macrophage polarization NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR IL4 extracellular protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 f We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription SIGNOR-254497 0.419 SIGNOR-M1M2 Macrophage polarization JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.813 SIGNOR-M1M2 Macrophage polarization KDM6B protein O15054 UNIPROT IRF4 factor protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 22025054 t lperfetto JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic. SIGNOR-249540 0.44 SIGNOR-M1M2 Macrophage polarization JAK2 protein O60674 UNIPROT STAT6 factor protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 t lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249532 0.659 SIGNOR-M1M2 Macrophage polarization IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-M1M2 Macrophage polarization IL4 extracellular protein P05112 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica IL-4R Is a 140-kd protein that binds il-4 with high affinity SIGNOR-100762 0.941 SIGNOR-M1M2 Macrophage polarization RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 t gcesareni These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108260 0.427 SIGNOR-M1M2 Macrophage polarization RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108257 0.427 SIGNOR-M1M2 Macrophage polarization IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249506 0.694 SIGNOR-M1M2 Macrophage polarization IL13 extracellular protein P35225 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. SIGNOR-100753 0.892 SIGNOR-M1M2 Macrophage polarization IL13 extracellular protein P35225 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates activity binding 9606 19880493 t lperfetto IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair. SIGNOR-249528 0.892 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 f lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 0.7 SIGNOR-M1M2 Macrophage polarization PPARG factor protein P37231 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249555 0.596 SIGNOR-M1M2 Macrophage polarization IL10 extracellular protein P22301 UNIPROT IL10RA receptor protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 0.911 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates activity 10090 24948596 f IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity SIGNOR-254682 0.534 SIGNOR-M1M2 Macrophage polarization PPARG factor protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249556 0.39 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17093501 t lperfetto We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent. SIGNOR-249570 0.624 SIGNOR-M1M2 Macrophage polarization IL10RA receptor protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 t lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-249545 0.418 SIGNOR-M1M2 Macrophage polarization STAT6 factor protein P42226 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000801 10982806 t lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site SIGNOR-249553 0.428 SIGNOR-M1M2 Macrophage polarization IFNG extracellular protein P01579 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 10090 23667107 f Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide. SIGNOR-255937 0.443 SIGNOR-M1M2 Macrophage polarization TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-M1M2 Macrophage polarization IFNG extracellular protein P01579 UNIPROT IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249487 0.757 SIGNOR-M1M2 Macrophage polarization KDM6B protein O15054 UNIPROT M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249563 0.7 SIGNOR-MC mTOR in cancer RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity relocalization 9606 20381137 t gcesareni The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb SIGNOR-228158 0.675 SIGNOR-MC mTOR in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-MC mTOR in cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-251983 0.634 SIGNOR-MC mTOR in cancer TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-MC mTOR in cancer INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR MYC factor protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256171 0.364 SIGNOR-MC mTOR in cancer IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 BTO:0000551 20966354 t lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. SIGNOR-256170 0.757 SIGNOR-MC mTOR in cancer AminoAcids extracellular stimulus SIGNOR-ST5 SIGNOR LAMTOR complex SIGNOR-C26 SIGNOR up-regulates 9606 BTO:0000007 SIGNOR-C3 20381137 f lperfetto The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids SIGNOR-228152 0.7 SIGNOR-MC mTOR in cancer PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-MC mTOR in cancer RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 t lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. SIGNOR-232208 0.791 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252454 0.634 SIGNOR-MC mTOR in cancer INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-MC mTOR in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252430 0.8 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252448 0.634 SIGNOR-MC mTOR in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-MC mTOR in cancer mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-MC mTOR in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-217008 0.634 SIGNOR-MC mTOR in cancer mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252451 0.634 SIGNOR-MC mTOR in cancer LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. SIGNOR-228155 0.871 SIGNOR-MC mTOR in cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-MC mTOR in cancer mTORC1 complex SIGNOR-C3 SIGNOR MYC factor protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256172 0.353 SIGNOR-MC mTOR in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-MC mTOR in cancer AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-MC mTOR in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-MCAPO Mitochondrial Control of Apoptosis PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.617 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-MCAPO Mitochondrial Control of Apoptosis APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . SIGNOR-135381 0.953 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1 SIGNOR-133823 0.807 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 t lperfetto Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. SIGNOR-178679 0.955 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000093 22464442 t lperfetto Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer. SIGNOR-209675 0.85 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.784 SIGNOR-MCAPO Mitochondrial Control of Apoptosis Survival Factors extracellular stimulus SIGNOR-ST8 SIGNOR BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 9346240 f lperfetto Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. SIGNOR-209693 0.7 SIGNOR-MCAPO Mitochondrial Control of Apoptosis APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 t gcesareni During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation. SIGNOR-53579 0.953 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-MCAPO Mitochondrial Control of Apoptosis APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. SIGNOR-53576 0.953 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-126727 0.515 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TP53 factor protein P04637 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19879762 t lperfetto As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5. SIGNOR-209687 0.265 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. SIGNOR-133829 0.955 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 t amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. SIGNOR-73902 0.817 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-MCAPO Mitochondrial Control of Apoptosis NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity 9606 19879762 t lperfetto BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis SIGNOR-209684 0.2 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 t lperfetto We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. SIGNOR-178676 0.807 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.935 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-173429 0.784 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. SIGNOR-133808 0.644 SIGNOR-MCAPO Mitochondrial Control of Apoptosis RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 21525013 t amattioni Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex SIGNOR-173432 0.906 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.787 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.615 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.838 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-MCAPO Mitochondrial Control of Apoptosis RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 12887920 t amattioni Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex SIGNOR-104255 0.906 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.787 SIGNOR-MCAPO Mitochondrial Control of Apoptosis ER stress extracellular stimulus SIGNOR-ST9 SIGNOR BBC3 protein Q9BXH1 UNIPROT up-regulates 9606 22492984 f miannu Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196938 0.7 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.59 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 7834748 t lperfetto Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored. SIGNOR-249617 0.838 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.787 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.789 SIGNOR-MCAPO Mitochondrial Control of Apoptosis DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR TP53 factor protein P04637 UNIPROT up-regulates quantity 9606 19879762 f lperfetto In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus. SIGNOR-209690 0.7 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0001938 11463392 t lperfetto Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release SIGNOR-109506 0.644 SIGNOR-MCAPO Mitochondrial Control of Apoptosis FAS receptor protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.906 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.787 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-MCAPO Mitochondrial Control of Apoptosis TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BBC3 protein Q9BXH1 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis. SIGNOR-133811 0.749 SIGNOR-MCAPO Mitochondrial Control of Apoptosis CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.617 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133820 0.807 SIGNOR-MCAPO Mitochondrial Control of Apoptosis BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1. SIGNOR-56399 0.836 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272975 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. SIGNOR-236321 0.595 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LAT receptor protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-252734 0.401 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MTOR protein P42345 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000661 34535949 t Barakat Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616 SIGNOR-275430 0.354 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102507 0.798 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 12954613 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. SIGNOR-100254 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Class I MHC:Antigen extracellular complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT up-regulates activity binding 9606 21954283 t scontino Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands. SIGNOR-267991 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CD274 extracellular protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 t miannu Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion. SIGNOR-82604 0.935 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C. SIGNOR-248936 0.328 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT up-regulates activity phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 t Barakat Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562. SIGNOR-274134 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 9606 21149567 t gcesareni Mff functions as an essential factor in mitochondrial recruitment of Drp1. SIGNOR-245957 0.628 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259932 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LAT receptor protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.801 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101115 0.924 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MFN1 protein Q8IWA4 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272984 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247018 0.763 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 factor protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes SIGNOR-252313 0.817 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Calcineurin complex SIGNOR-C155 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-252315 0.276 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion OPA1 protein O60313 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272987 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PLCG1 protein P19174 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176609 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT up-regulates activity binding 9534 1423621 t We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction. SIGNOR-252304 0.681 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LAT receptor protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 23150273 t Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling SIGNOR-251520 0.797 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDCD1 protein Q15116 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 28286692 f Barakat Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. SIGNOR-275413 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272976 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion FYN protein P06241 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-148931 0.737 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 receptor protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 f Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer SIGNOR-260766 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 15854902 t lperfetto Rheb binds and regulates the mTOR kinase. SIGNOR-135770 0.949 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 t lperfetto P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation SIGNOR-46851 0.744 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CD28 receptor protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation SIGNOR-202706 0.69 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) SIGNOR-174882 0.989 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. SIGNOR-226628 0.597 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDCD1 protein Q15116 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 f Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 SIGNOR-275410 0.27 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-252337 0.568 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Class II MHC:Antigen extracellular complex SIGNOR-C429 SIGNOR TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 t scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. SIGNOR-267992 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDCD1 protein Q15116 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 f Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 SIGNOR-275411 0.267 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PTPRC receptor protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity SIGNOR-248350 0.79 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors SIGNOR-249374 0.563 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259935 0.345 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000007 25658205 t Barakat Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. SIGNOR-275407 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176606 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDCD1 protein Q15116 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 f Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. SIGNOR-275408 0.356 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PTPRC receptor protein P08575 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction. SIGNOR-248352 0.719 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. SIGNOR-149182 0.749 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CTLA4 protein P16410 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 f Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. SIGNOR-275409 0.589 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion EIF4E protein P06730 UNIPROT MTFP1 protein Q9UDX5 UNIPROT up-regulates activity translation regulation 10090 BTO:0002572 28918902 t Barakat In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1 SIGNOR-275429 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Class I MHC:Antigen extracellular complex SIGNOR-C426 SIGNOR TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 t scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. SIGNOR-267993 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MTFP1 protein Q9UDX5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 10090 BTO:0002572 28918902 f Barakat Regardless of the precise mechanism, our data establish MTFP1 as an essential regulator of mitochondrial fission through the modulation of DRP1 phosphorylation and recruitment to the mitochondrion. SIGNOR-275449 0.412 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion NFATC1 factor protein O95644 UNIPROT IL2 extracellular protein P60568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10022916 t Barakat Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses. SIGNOR-275405 0.59 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-217008 0.634 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT CD28 receptor protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-198755 0.745 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MTOR protein P42345 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 f apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction SIGNOR-255108 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MFN2 protein O95140 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272985 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CTLA4 protein P16410 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 26086965 f Barakat Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion SIGNOR-275415 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LAG3 protein P18627 UNIPROT Class II MHC:Antigen extracellular complex SIGNOR-C429 SIGNOR down-regulates activity binding 9606 BTO:0000782 35413245 t Barakat Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity SIGNOR-275412 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity. SIGNOR-20371 0.512 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PIP3 receptor smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252430 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251381 0.744 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion AP1 factor complex SIGNOR-C154 SIGNOR CD3 complex SIGNOR-C432 SIGNOR up-regulates activity binding 9606 16473826 t scontino When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery. SIGNOR-267994 0.326 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell). SIGNOR-198822 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 t lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission SIGNOR-262551 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126066 0.387 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PRKCA protein P17252 UNIPROT NFATC1 factor protein O95644 UNIPROT down-regulates activity phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. SIGNOR-249175 0.393 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion Class II MHC:Antigen extracellular complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT up-regulates activity binding 9606 31001252 t scontino Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens SIGNOR-267990 0.2 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc. SIGNOR-272983 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LAG3 protein P18627 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 27192565 f Barakat Lag-3, Tim-3, and TIGIT are highly expressed on dysfunctional or exhausted T cells in chronic diseases such as chronic viral infection and cancer. SIGNOR-275414 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion NFATC1 factor protein O95644 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates activity 10358178 f The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. SIGNOR-252344 0.7 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR up-regulates activity phosphorylation 9606 8626561 t The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex SIGNOR-252305 0.63 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199. SIGNOR-99310 0.535 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-MD Mitochondrial dynamics in T cell exhaustion PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT down-regulates activity 9606 BTO:0000782 34535949 f Barakat Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases. SIGNOR-275406 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244862 0.743 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249572 0.2 SIGNOR-MM Malignant Melanoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 f lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis SIGNOR-43927 0.434 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68647 0.2 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244858 0.743 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.812 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-247992 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 t lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-249573 0.2 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.857 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249574 0.2 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT MITF factor protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 10841026 t lperfetto Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription. SIGNOR-249619 0.621 SIGNOR-MM Malignant Melanoma RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-MM Malignant Melanoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 t The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. SIGNOR-251474 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 SIGNOR-MM Malignant Melanoma BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity binding -1 10949026 t lperfetto Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival. SIGNOR-81125 0.838 SIGNOR-MM Malignant Melanoma NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 t lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. SIGNOR-244497 0.2 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT CREB1 factor protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. SIGNOR-248543 0.455 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated SIGNOR-102641 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. SIGNOR-248283 0.632 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 SIGNOR-MM Malignant Melanoma UV stress extracellular stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. SIGNOR-252376 0.7 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-MM Malignant Melanoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-MM Malignant Melanoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131391 0.2 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.857 SIGNOR-MM Malignant Melanoma PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.812 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248546 0.2 SIGNOR-MM Malignant Melanoma BAK1 protein Q16611 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261493 0.7 SIGNOR-MM Malignant Melanoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131387 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 factor protein Q01094 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233526 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF factor protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation. SIGNOR-249575 0.2 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131407 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity phosphorylation Tyr570 INGNNYVyIDPTQLP 9606 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated SIGNOR-102637 0.2 SIGNOR-MM Malignant Melanoma SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256260 0.7 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-MM Malignant Melanoma RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251469 0.2 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002552 17000778 t lperfetto We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis SIGNOR-149815 0.338 SIGNOR-MM Malignant Melanoma SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.769 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.857 SIGNOR-MM Malignant Melanoma NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175222 0.835 SIGNOR-MM Malignant Melanoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-MM Malignant Melanoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.838 SIGNOR-MM Malignant Melanoma MITF factor protein O75030 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 12086670 t lperfetto MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF SIGNOR-249618 0.45 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131399 0.2 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001009 10753867 f lperfetto Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival. SIGNOR-76558 0.434 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-MM Malignant Melanoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68643 0.2 SIGNOR-MM Malignant Melanoma KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity binding 9606 17259966 t miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells SIGNOR-254946 0.933 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131395 0.2 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.789 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-MM Malignant Melanoma KITLG extracellular protein P21583 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. SIGNOR-21193 0.933 SIGNOR-MM Malignant Melanoma E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.857 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244494 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254953 0.7 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-MM Malignant Melanoma KIT receptor protein P10721 UNIPROT KIT receptor protein P10721 UNIPROT up-regulates activity phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated SIGNOR-102633 0.2 SIGNOR-MM Malignant Melanoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-MM Malignant Melanoma BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak SIGNOR-152980 0.656 SIGNOR-MM Malignant Melanoma PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16205321 f gcesareni The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression. SIGNOR-140911 0.373 SIGNOR-MM Malignant Melanoma RPS6KA5 protein O75582 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.721 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.857 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-MM Malignant Melanoma BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 7834748 t lperfetto Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored. SIGNOR-249617 0.838 SIGNOR-MM Malignant Melanoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-MM Malignant Melanoma BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-MM Malignant Melanoma CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251470 0.2 SIGNOR-MM Malignant Melanoma TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-MM Malignant Melanoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 SIGNOR-MM Malignant Melanoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-MM Malignant Melanoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.857 SIGNOR-MM Malignant Melanoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-MM Malignant Melanoma MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-MM Malignant Melanoma PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 SIGNOR-mRNA_Maturation mRNA maturation CCR4-NOT complex complex SIGNOR-C439 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 31320642 t lperfetto CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. |The poly(A) tails at 3′ ends of eukaryotic mRNAs are crucial for their cytoplasmic stability and to enhance the initiation of translation. Newly synthesized metazoan mRNAs possess long poly(A) tails1, and following export to the cytoplasm the tails are reported to be ~60–80 nucleotides on average at steady state2. Poly(A) tails are also important for translational efficiency at the embryonic stage2 and the length of the poly(A) tail was reported to be correlated with translational efficiency3. The multisubunit CCR4-NOT complex is principally responsible for efficient processive shortening of poly(A) tails, or deadenylation, in addition to other function SIGNOR-268312 0.8 SIGNOR-mRNA_Maturation mRNA maturation Exon junction complex complex SIGNOR-C369 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 11532962 t lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay SIGNOR-268315 0.8 SIGNOR-mRNA_Maturation mRNA maturation Upf-EJC complex SIGNOR-C367 SIGNOR Nonsense-mediated mRNA decay phenotype SIGNOR-PH175 SIGNOR up-regulates 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1. the hUpf complex communicates with the EJC and triggers NMD in the cytoplasm. SIGNOR-265239 0.7 SIGNOR-mRNA_Maturation mRNA maturation Exon junction complex complex SIGNOR-C369 SIGNOR Upf-EJC complex SIGNOR-C367 SIGNOR up-regulates activity binding -1 18066079 t miannu Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC).  SIGNOR-265244 0.858 SIGNOR-mRNA_Maturation mRNA maturation mRNA_capping phenotype SIGNOR-PH178 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 f lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268317 0.7 SIGNOR-mRNA_Maturation mRNA maturation CPSF complex complex SIGNOR-C53 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity relocalization 9606 14749727 t lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-268323 0.785 SIGNOR-mRNA_Maturation mRNA maturation PABPC1 protein P11940 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268318 0.8 SIGNOR-mRNA_Maturation mRNA maturation RNGTT protein O60942 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates quantity chemical modification 9606 9512541 f lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi SIGNOR-268356 0.7 SIGNOR-mRNA_Maturation mRNA maturation Cap-binding complex complex SIGNOR-C440 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates relocalization 9606 32873578 t lperfetto The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. SIGNOR-268360 0.8 SIGNOR-mRNA_Maturation mRNA maturation RAMAC protein Q9BTL3 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity binding 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268344 0.2 SIGNOR-mRNA_Maturation mRNA maturation CSTF complex complex SIGNOR-C441 SIGNOR mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 10669729 f lperfetto Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. SIGNOR-268369 0.7 SIGNOR-mRNA_Maturation mRNA maturation PAPOLA protein P51003 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 f lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268325 0.7 SIGNOR-mRNA_Maturation mRNA maturation RNMT protein O43148 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates 9606 BTO:0000567 26942677 f lperfetto The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. SIGNOR-265503 0.7 SIGNOR-mRNA_Maturation mRNA maturation RNA Polymerase II factor complex SIGNOR-C391 SIGNOR precursor messenger RNA smallmolecule CHEBI:139356 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. SIGNOR-266176 0.8 SIGNOR-mRNA_Maturation mRNA maturation TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. SIGNOR-268345 0.7 SIGNOR-mRNA_Maturation mRNA maturation TUT4 protein Q5TAX3 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. SIGNOR-268355 0.7 SIGNOR-mRNA_Maturation mRNA maturation TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. SIGNOR-268354 0.7 SIGNOR-mRNA_Maturation mRNA maturation precursor messenger RNA smallmolecule CHEBI:139356 ChEBI messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity precursor of 9606 19224921 t lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268314 0.8 SIGNOR-mRNA_Maturation mRNA maturation RNA_splicing phenotype SIGNOR-PH201 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates 9606 32140746 f lperfetto The splicing of introns from nuclear precursors of message RNA (pre-mRNA) is executed by the spliceosome, a ribonucleoprotein (RNP) apparatus that first surfaced in the literature in 1985  SIGNOR-268402 0.7 SIGNOR-mRNA_Maturation mRNA maturation mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 f lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. SIGNOR-268322 0.7 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219273 0.924 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55701 0.924 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 t lperfetto S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability. SIGNOR-72682 0.96 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL -1 SIGNOR-C3 10567431 t lperfetto We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate SIGNOR-72357 0.96 SIGNOR-MS MTOR Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 9606 2550426 t lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. SIGNOR-23001 0.932 SIGNOR-MS MTOR Signaling EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101123 0.924 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR INSR receptor protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 22207502 t lperfetto Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. SIGNOR-216619 0.31 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106522 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101332 0.96 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219262 0.924 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-236709 0.911 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT TFEB factor protein P19484 UNIPROT down-regulates activity phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB. SIGNOR-248270 0.498 SIGNOR-MS MTOR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209940 0.48 SIGNOR-MS MTOR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250553 0.2 SIGNOR-MS MTOR Signaling RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 20006481 t lperfetto Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status. SIGNOR-162006 0.949 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101328 0.96 SIGNOR-MS MTOR Signaling IRS1 protein P35568 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10116 BTO:0001103 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). SIGNOR-175668 0.806 SIGNOR-MS MTOR Signaling PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-MS MTOR Signaling SREBF1 factor protein P36956 UNIPROT Lipogenesis phenotypesList phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 f lperfetto In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), SIGNOR-228614 0.7 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216499 0.464 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250558 0.2 SIGNOR-MS MTOR Signaling RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-153622 0.614 SIGNOR-MS MTOR Signaling RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-110917 0.367 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-236713 0.911 SIGNOR-MS MTOR Signaling PPARGC1A factor protein Q9UBK2 UNIPROT Mitochondrial_biogenesis phenotypesList phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 23277535 f gcesareni PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc SIGNOR-228618 0.7 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106514 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0002572 12782654 t lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. SIGNOR-101336 0.96 SIGNOR-MS MTOR Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-251526 0.778 SIGNOR-MS MTOR Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236649 0.503 SIGNOR-MS MTOR Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 SIGNOR-147948 0.8 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 10090 BTO:0001103 17609368 t gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter SIGNOR-228642 0.48 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-148903 0.782 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201530 0.96 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) SIGNOR-174882 0.989 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 0.2 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216647 0.48 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 17517883 t lperfetto The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)).PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp. SIGNOR-154956 0.901 SIGNOR-MS MTOR Signaling PIK3CA protein P42336 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. SIGNOR-65409 0.8 SIGNOR-MS MTOR Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser434 PPPSDAGsPFQSSPL 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-235797 0.503 SIGNOR-MS MTOR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0000944 SIGNOR-C3 17510057 t lperfetto mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389 SIGNOR-235507 0.96 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127908 0.782 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser212 EENGPPSsPDLDRIA -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to ser-183, mtorc1 also phosphorylates ser-212 and ser-221 in pras40 when assayed in vitro. SIGNOR-178124 0.901 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201538 0.96 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.911 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR up-regulates activity phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 t lperfetto GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation SIGNOR-217749 0.459 SIGNOR-MS MTOR Signaling INS extracellular protein P01308 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.932 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser221 DLDRIAAsMRALVLR -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. SIGNOR-178128 0.901 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 factor protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-244754 0.2 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR SREBF1 factor protein P36956 UNIPROT down-regulates phosphorylation 9606 21892142 t lperfetto Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation SIGNOR-216564 0.327 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. SIGNOR-232236 0.2 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 17609368 t gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter SIGNOR-228646 0.48 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.911 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C3 19690328 t lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. SIGNOR-187611 0.843 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 t lperfetto The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo. SIGNOR-184959 0.989 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 t lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. SIGNOR-135176 0.936 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 t lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. SIGNOR-51216 0.782 SIGNOR-MS MTOR Signaling ULK1 protein O75385 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-217484 0.464 SIGNOR-MS MTOR Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236667 0.503 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101119 0.924 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.911 SIGNOR-MS MTOR Signaling PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242637 0.934 SIGNOR-MS MTOR Signaling EIF4E protein P06730 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236599 0.782 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates quantity by expression phosphorylation 10090 BTO:0000011 12270934 t lperfetto Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression. SIGNOR-235334 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified. SIGNOR-178120 0.901 SIGNOR-MS MTOR Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236645 0.503 SIGNOR-MS MTOR Signaling LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. SIGNOR-228155 0.871 SIGNOR-MS MTOR Signaling RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb SIGNOR-228657 0.802 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167180 0.924 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR SREBF1 factor protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 21459323 t lperfetto Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 SIGNOR-216533 0.327 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 9204908 t miannu MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. SIGNOR-250292 0.924 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 SIGNOR-C3 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-80797 0.924 SIGNOR-MS MTOR Signaling RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-171247 0.614 SIGNOR-MS MTOR Signaling RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 15854902 t lperfetto Rheb binds and regulates the mTOR kinase. SIGNOR-135770 0.949 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235975 0.911 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin. SIGNOR-127904 0.782 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19864431 t lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) SIGNOR-188920 0.989 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209936 0.48 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233560 0.2 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser235 IAKRRRLsSLRASTS 10090 15809305 t lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. SIGNOR-135172 0.936 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-106526 0.2 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236745 0.911 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. SIGNOR-226714 0.924 SIGNOR-MS MTOR Signaling RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-171243 0.614 SIGNOR-MS MTOR Signaling RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-153618 0.614 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127203 0.782 SIGNOR-MS MTOR Signaling TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.914 SIGNOR-MS MTOR Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-236725 0.911 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR PPARGC1A factor protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216651 0.48 SIGNOR-MS MTOR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101115 0.924 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.911 SIGNOR-MS MTOR Signaling GSK3B protein P49841 UNIPROT SREBF1 factor protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 t lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. SIGNOR-236030 0.503 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216495 0.464 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. SIGNOR-216464 0.464 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 t lperfetto Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation SIGNOR-188924 0.989 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250557 0.2 SIGNOR-MS MTOR Signaling AminoAcids extracellular stimulus SIGNOR-ST5 SIGNOR LAMTOR complex SIGNOR-C26 SIGNOR up-regulates 9606 BTO:0000007 SIGNOR-C3 20381137 f lperfetto The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids SIGNOR-228152 0.7 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT INSR receptor protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 0.2 SIGNOR-MS MTOR Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216491 0.464 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201534 0.96 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-167184 0.924 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216457 0.464 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219266 0.924 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21460634 t lperfetto mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13. SIGNOR-183903 0.843 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101127 0.924 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. SIGNOR-235983 0.911 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219257 0.924 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0002181 SIGNOR-C3 10942774 t lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. SIGNOR-226710 0.924 SIGNOR-MS MTOR Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216461 0.464 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154810 0.924 SIGNOR-MS MTOR Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-251983 0.634 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236595 0.782 SIGNOR-MS MTOR Signaling INSR receptor protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells SIGNOR-235971 0.911 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55697 0.924 SIGNOR-MS MTOR Signaling AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216453 0.464 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154814 0.924 SIGNOR-MS MTOR Signaling MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 t lperfetto When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk. SIGNOR-172541 0.843 SIGNOR-MS MTOR Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-251982 0.634 SIGNOR-MS MTOR Signaling RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127912 0.782 SIGNOR-MSP Multiple sclerosis IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-MSP Multiple sclerosis IFNG extracellular protein P01579 UNIPROT Demyelination phenotypesList phenotype SIGNOR-PH155 SIGNOR up-regulates 10090 BTO:0000227 24507514 f miannu Beside its wellknown antiviral and proinflammatory action, overexpression of IFN-g in the CNS could participate in demyelination. Transgenic overexpression of IFN-g in the mouse by CNS oligodendrocytes led to chronic demyelination that may be severe SIGNOR-263833 0.7 SIGNOR-MSP Multiple sclerosis SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.701 SIGNOR-MSP Multiple sclerosis AP1 factor complex SIGNOR-C154 SIGNOR IL6 extracellular protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254513 0.629 SIGNOR-MSP Multiple sclerosis TNFRSF21 receptor protein O75509 UNIPROT ROS extracellular stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. SIGNOR-263830 0.7 SIGNOR-MSP Multiple sclerosis M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR TNF extracellular protein P01375 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263826 0.7 SIGNOR-MSP Multiple sclerosis TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-42984 0.889 SIGNOR-MSP Multiple sclerosis IL1B extracellular protein P01584 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261026 0.7 SIGNOR-MSP Multiple sclerosis nitric oxide smallmolecule CHEBI:16480 ChEBI NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates 9606 BTO:0001103 20219869 t apalma Similarly, exposure of cells to oxidative stress, in particular, nitric oxide (NO) or peroxynitrite (ONOO), can activate NF-kB and cause its translocation. SIGNOR-255350 0.8 SIGNOR-MSP Multiple sclerosis CD40 extracellular protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000776 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-179473 0.836 SIGNOR-MSP Multiple sclerosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 17151142 t miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 0.923 SIGNOR-MSP Multiple sclerosis M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR IL4 extracellular protein P05112 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263822 0.7 SIGNOR-MSP Multiple sclerosis TNFRSF1A receptor protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 t We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256251 0.826 SIGNOR-MSP Multiple sclerosis ROS extracellular stimulus SIGNOR-ST2 SIGNOR Demyelination phenotypesList phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 f miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction SIGNOR-263828 0.7 SIGNOR-MSP Multiple sclerosis TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-MSP Multiple sclerosis IL4R receptor protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 t lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. SIGNOR-249529 0.705 SIGNOR-MSP Multiple sclerosis AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-MSP Multiple sclerosis INHBA extracellular protein P08476 UNIPROT ACVR2B receptor protein Q13705 UNIPROT up-regulates activity binding 9606 8622651 t gcesareni Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. SIGNOR-235142 0.774 SIGNOR-MSP Multiple sclerosis IL10 extracellular protein P22301 UNIPROT IL10RA receptor protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 t lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 0.911 SIGNOR-MSP Multiple sclerosis TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-MSP Multiple sclerosis nitric oxide smallmolecule CHEBI:16480 ChEBI M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR up-regulates 24669294 f apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines SIGNOR-255556 0.7 SIGNOR-MSP Multiple sclerosis IL1B extracellular protein P01584 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 BTO:0002417 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263820 0.572 SIGNOR-MSP Multiple sclerosis M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR IL10 extracellular protein P22301 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263823 0.7 SIGNOR-MSP Multiple sclerosis TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-MSP Multiple sclerosis TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.82 SIGNOR-MSP Multiple sclerosis SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256180 0.528 SIGNOR-MSP Multiple sclerosis ACVR2A receptor protein P27037 UNIPROT ACVR1B receptor protein P36896 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12682303 t acerquone In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase SIGNOR-99995 0.667 SIGNOR-MSP Multiple sclerosis M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263825 0.7 SIGNOR-MSP Multiple sclerosis IL17A extracellular protein Q16552 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR up-regulates activity binding 9606 BTO:0001946 32024054 t lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. SIGNOR-261337 0.799 SIGNOR-MSP Multiple sclerosis ACVR1B receptor protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 14517293 t gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235157 0.795 SIGNOR-MSP Multiple sclerosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  SIGNOR-249519 0.7 SIGNOR-MSP Multiple sclerosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR IL6 extracellular protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254511 0.622 SIGNOR-MSP Multiple sclerosis nitric oxide smallmolecule CHEBI:16480 ChEBI Demyelination phenotypesList phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 f miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction SIGNOR-263829 0.7 SIGNOR-MSP Multiple sclerosis JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 0.794 SIGNOR-MSP Multiple sclerosis CD40 extracellular protein P25942 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 f fstefani Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development SIGNOR-189109 0.7 SIGNOR-MSP Multiple sclerosis IL6ST receptor protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 t milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. SIGNOR-202036 0.66 SIGNOR-MSP Multiple sclerosis ACVR2B receptor protein Q13705 UNIPROT ACVR1B receptor protein P36896 UNIPROT up-regulates activity phosphorylation Thr206 VQRTVARtIVLQEII 9606 8622651 t miannu Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. SIGNOR-235146 0.671 SIGNOR-MSP Multiple sclerosis TNFRSF21 receptor protein O75509 UNIPROT Demyelination phenotypesList phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 32454942 f miannu Next to inhibition of sTNF/TNFR1 signaling, specific activation of TNFR2 may hold promise as a new MS therapy. Indeed, TNF promotes proliferation of oligodendrocyte progenitors and remyelination via TNFR2 SIGNOR-263832 0.7 SIGNOR-MSP Multiple sclerosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-MSP Multiple sclerosis IL6 extracellular protein P05231 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260256 0.7 SIGNOR-MSP Multiple sclerosis STAT3 protein P40763 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263821 0.7 SIGNOR-MSP Multiple sclerosis IL6 extracellular protein P05231 UNIPROT IL6R receptor protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 0.916 SIGNOR-MSP Multiple sclerosis IFNG extracellular protein P01579 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260259 0.7 SIGNOR-MSP Multiple sclerosis NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-MSP Multiple sclerosis IL6R receptor protein P08887 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 t gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 0.736 SIGNOR-MSP Multiple sclerosis T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR IL17A extracellular protein Q16552 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263819 0.7 SIGNOR-MSP Multiple sclerosis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 14732063 t miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253593 0.923 SIGNOR-MSP Multiple sclerosis SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256181 0.628 SIGNOR-MSP Multiple sclerosis IFNG extracellular protein P01579 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261024 0.7 SIGNOR-MSP Multiple sclerosis NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-MSP Multiple sclerosis IL17R complex complex SIGNOR-C260 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 10090 BTO:0000944 8777726 f lperfetto 3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity. SIGNOR-261338 0.2 SIGNOR-MSP Multiple sclerosis INHBA extracellular protein P08476 UNIPROT ACVR2A receptor protein P27037 UNIPROT up-regulates activity binding 9606 1646080 t gcesareni A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1. SIGNOR-235138 0.805 SIGNOR-MSP Multiple sclerosis T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR IFNG extracellular protein P01579 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 f miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology SIGNOR-263818 0.7 SIGNOR-MSP Multiple sclerosis SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-MSP Multiple sclerosis M1_polarization extracellular phenotype SIGNOR-PH54 SIGNOR IFNG extracellular protein P01579 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263827 0.7 SIGNOR-MSP Multiple sclerosis ACVR1B receptor protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 14517293 t gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway SIGNOR-235160 0.729 SIGNOR-MSP Multiple sclerosis IL10RA receptor protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 t IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. SIGNOR-253589 0.798 SIGNOR-MSP Multiple sclerosis IL4 extracellular protein P05112 UNIPROT IL4R receptor protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 t lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. SIGNOR-249527 0.941 SIGNOR-MSP Multiple sclerosis TNF extracellular protein P01375 UNIPROT Demyelination phenotypesList phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 24507514 f miannu TNF-a is the most comprehensively studied cytokine in both EAE and MS. Most TNF-a overexpressing transgenic animals showed spontaneous pathology, characterized by progressive demyelination and macrophage infiltration SIGNOR-263834 0.7 SIGNOR-MSP Multiple sclerosis TNF extracellular protein P01375 UNIPROT TNFRSF21 receptor protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain. SIGNOR-59745 0.348 SIGNOR-MSP Multiple sclerosis RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-MSP Multiple sclerosis M2_polarization extracellular phenotype SIGNOR-PH55 SIGNOR TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263824 0.7 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.864 SIGNOR-NFKBC NF-KB Canonical TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-NFKBC NF-KB Canonical IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-NFKBC NF-KB Canonical TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205458 0.93 SIGNOR-NFKBC NF-KB Canonical TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 0.933 SIGNOR-NFKBC NF-KB Canonical TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-NFKBC NF-KB Canonical NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-NFKBC NF-KB Canonical UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 11057907 t lperfetto We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin SIGNOR-83603 0.686 SIGNOR-NFKBC NF-KB Canonical TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 0.889 SIGNOR-NFKBC NF-KB Canonical MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-NFKBC NF-KB Canonical UBE2N protein P61088 UNIPROT UBE2V1 protein Q13404 UNIPROT up-regulates activity binding 9606 20551964 t lperfetto Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains. SIGNOR-166177 0.849 SIGNOR-NFKBC NF-KB Canonical TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 t lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 0.933 SIGNOR-NFKBC NF-KB Canonical NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 0.7 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-NFKBC NF-KB Canonical CYLD protein Q9NQC7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates deubiquitination 9606 BTO:0001253 12917689 t lperfetto The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6. SIGNOR-117856 0.781 SIGNOR-NFKBC NF-KB Canonical TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 t lperfetto Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages SIGNOR-120268 0.933 SIGNOR-NFKBC NF-KB Canonical CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity deubiquitination 9606 12917691 t lperfetto Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract) SIGNOR-117860 0.661 SIGNOR-NFKBC NF-KB Canonical NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-NFKBC NF-KB Canonical NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-NFKBC NF-KB Canonical FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 SIGNOR-NFKBC NF-KB Canonical FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-173429 0.784 SIGNOR-NFKBC NF-KB Canonical RNF11 protein Q9Y3C5 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0000150 19131965 t lperfetto Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation. SIGNOR-183188 0.575 SIGNOR-NFKBC NF-KB Canonical SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity ubiquitination 9534 11295495 t lperfetto The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235305 0.488 SIGNOR-NFKBC NF-KB Canonical FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 SIGNOR-NFKBC NF-KB Canonical IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-NFKBC NF-KB Canonical TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-NFKBC NF-KB Canonical TAX1BP1 protein Q86VP1 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 10435631 t lperfetto Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb. SIGNOR-69921 0.668 SIGNOR-NFKBC NF-KB Canonical FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.784 SIGNOR-NFKBC NF-KB Canonical IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 t lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 0.864 SIGNOR-NFKBC NF-KB Canonical TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.935 SIGNOR-NFKBC NF-KB Canonical TRAF6 protein Q9Y4K3 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205461 0.701 SIGNOR-NFKBC NF-KB Canonical TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 18164316 t lperfetto A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6 SIGNOR-160223 0.688 SIGNOR-NFKBC NF-KB Canonical FAS receptor protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.906 SIGNOR-NFKBC NF-KB Canonical TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.864 SIGNOR-NFKBC NF-KB Canonical TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-NFKBC NF-KB Canonical IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-NFKBC NF-KB Canonical TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-NFKBC NF-KB Canonical MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 t lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a SIGNOR-217445 0.713 SIGNOR-NFKBC NF-KB Canonical RIPK1 protein Q13546 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways. SIGNOR-216325 0.646 SIGNOR-NFKBC NF-KB Canonical ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 18246070 t lperfetto Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract) SIGNOR-160621 0.287 SIGNOR-NFKBC NF-KB Canonical TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 t lperfetto We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1. SIGNOR-120325 0.824 SIGNOR-NFKBNC NF-KB Non Canonical TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000785 15084608 t lperfetto We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124233 0.564 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-217433 0.707 SIGNOR-NFKBNC NF-KB Non Canonical TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000459 18621737 t lperfetto Through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2. SIGNOR-179449 0.866 SIGNOR-NFKBNC NF-KB Non Canonical SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 factor protein Q00653 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 14676825 t lperfetto Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. SIGNOR-217175 0.53 SIGNOR-NFKBNC NF-KB Non Canonical TNFSF13B extracellular protein Q9Y275 UNIPROT TNFRSF13C receptor protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000782 15851487 t lperfetto Baff specifically binds baff receptor SIGNOR-135713 0.779 SIGNOR-NFKBNC NF-KB Non Canonical CD40 extracellular protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000776 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-179473 0.836 SIGNOR-NFKBNC NF-KB Non Canonical BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18997794 t lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. SIGNOR-182128 0.866 SIGNOR-NFKBNC NF-KB Non Canonical TNFSF13B extracellular protein Q9Y275 UNIPROT TNFRSF13C receptor protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 15644327 t lperfetto Baff interacts with baff receptor (baffr). SIGNOR-133210 0.779 SIGNOR-NFKBNC NF-KB Non Canonical RELB factor protein Q01201 UNIPROT B_cell_maturation phenotypesList phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 26385063 f miannu We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. SIGNOR-263655 0.7 SIGNOR-NFKBNC NF-KB Non Canonical TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 t lperfetto Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation. SIGNOR-167066 0.564 SIGNOR-NFKBNC NF-KB Non Canonical TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 15084608 t lperfetto Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124236 0.652 SIGNOR-NFKBNC NF-KB Non Canonical CD40LG extracellular protein P29965 UNIPROT CD40 extracellular protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0003076 19426221 t lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner .cd40 binds its ligand cd40l. SIGNOR-185660 0.927 SIGNOR-NFKBNC NF-KB Non Canonical NFKB2 factor protein Q00653 UNIPROT RELB factor protein Q01201 UNIPROT up-regulates activity binding 9606 19098713 t lperfetto The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator. SIGNOR-182835 0.744 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation 9606 20651737 t lperfetto Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes. SIGNOR-167060 0.678 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT NFKB2 factor protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 t lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 SIGNOR-105557 0.662 SIGNOR-NFKBNC NF-KB Non Canonical LTBR receptor protein P36941 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 12571250 t lperfetto Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. SIGNOR-97950 0.563 SIGNOR-NFKBNC NF-KB Non Canonical TNFRSF13C receptor protein Q96RJ3 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000776;BTO:0000785 20889926 t lperfetto Activation of br3 induces recruitment and degradation of traf3. SIGNOR-168199 0.749 SIGNOR-NFKBNC NF-KB Non Canonical TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 8548810 t lperfetto The c-iaps associate with traf1 and traf3 SIGNOR-39527 0.866 SIGNOR-NFKBNC NF-KB Non Canonical CD40LG extracellular protein P29965 UNIPROT CD40 extracellular protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000776 12324477 t lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l. SIGNOR-93432 0.927 SIGNOR-NFKBNC NF-KB Non Canonical CD40 extracellular protein P25942 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 9606 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-250560 0.916 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser176 AKDVDQGsLCTSFVG 9606 SIGNOR-C14 9520446 t lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-55942 0.678 SIGNOR-NFKBNC NF-KB Non Canonical TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 9020361 t lperfetto NIK binds to Traf2 and stimulates NF-kappaB activity. SIGNOR-46215 0.564 SIGNOR-NFKBNC NF-KB Non Canonical CHUK protein O15111 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 t gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. SIGNOR-164506 0.77 SIGNOR-NFKBNC NF-KB Non Canonical CHUK protein O15111 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization phosphorylation Thr559 TGDYIPGtETHMAPE 9606 BTO:0000776 20501937 t lperfetto Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis. SIGNOR-165622 0.678 SIGNOR-NFKBNC NF-KB Non Canonical CHUK protein O15111 UNIPROT NFKB2 factor protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 t lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. SIGNOR-124226 0.785 SIGNOR-NFKBNC NF-KB Non Canonical LTBR receptor protein P36941 UNIPROT B_cell_maturation phenotypesList phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 17633025 f lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. SIGNOR-156899 0.7 SIGNOR-NFKBNC NF-KB Non Canonical BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 t lperfetto Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex. SIGNOR-167057 0.866 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT NFKB2 factor protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 t lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 SIGNOR-105553 0.662 SIGNOR-NFKBNC NF-KB Non Canonical MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 9520446 t lperfetto NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. SIGNOR-55946 0.678 SIGNOR-NFKBNC NF-KB Non Canonical CHUK protein O15111 UNIPROT NFKB2 factor protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 t lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. SIGNOR-124230 0.785 SIGNOR-NFKBNC NF-KB Non Canonical TNFRSF13C receptor protein Q96RJ3 UNIPROT B_cell_maturation phenotypesList phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 BTO:0000776 24432023 f lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. SIGNOR-204361 0.7 SIGNOR-NFKBNC NF-KB Non Canonical LTB extracellular protein Q06643 UNIPROT LTBR receptor protein P36941 UNIPROT up-regulates activity binding 9606 BTO:0000782 BTO:0000975 7995952 t lperfetto These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor. SIGNOR-35759 0.835 SIGNOR-NM Nucleotide Biosynthesis ATIC protein P31939 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267326 0.8 SIGNOR-NM Nucleotide Biosynthesis NFE2L2 factor protein Q16236 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267358 0.2 SIGNOR-NM Nucleotide Biosynthesis N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267307 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267435 0.8 SIGNOR-NM Nucleotide Biosynthesis PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267295 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267191 0.8 SIGNOR-NM Nucleotide Biosynthesis ATP synthase complex SIGNOR-C264 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity chemical modification 9606 21874297 t miannu Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. SIGNOR-261410 0.8 SIGNOR-NM Nucleotide Biosynthesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Thr456 KVYFLPItPHYVTQV -1 17485345 t miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  SIGNOR-267441 0.2 SIGNOR-NM Nucleotide Biosynthesis PAICS protein P22234 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267322 0.8 SIGNOR-NM Nucleotide Biosynthesis UMPS protein P11172 UNIPROT UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267440 0.8 SIGNOR-NM Nucleotide Biosynthesis PFAS protein O15067 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267311 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267316 0.8 SIGNOR-NM Nucleotide Biosynthesis GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267300 0.8 SIGNOR-NM Nucleotide Biosynthesis ATP smallmolecule CHEBI:15422 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-268079 0.8 SIGNOR-NM Nucleotide Biosynthesis ATIC protein P31939 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267329 0.8 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267375 0.301 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267426 0.8 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. SIGNOR-267381 0.2 SIGNOR-NM Nucleotide Biosynthesis CPS1 protein P31327 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 15096496 t CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules SIGNOR-267192 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267328 0.8 SIGNOR-NM Nucleotide Biosynthesis orotate smallmolecule CHEBI:30839 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267434 0.8 SIGNOR-NM Nucleotide Biosynthesis L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267320 0.8 SIGNOR-NM Nucleotide Biosynthesis CAD protein P27708 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267421 0.8 SIGNOR-NM Nucleotide Biosynthesis 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267302 0.8 SIGNOR-NM Nucleotide Biosynthesis GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267304 0.8 SIGNOR-NM Nucleotide Biosynthesis 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-268104 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268072 0.8 SIGNOR-NM Nucleotide Biosynthesis L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity precursor of 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-268131 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-268109 0.8 SIGNOR-NM Nucleotide Biosynthesis (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity precursor of 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267428 0.8 SIGNOR-NM Nucleotide Biosynthesis 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267313 0.8 SIGNOR-NM Nucleotide Biosynthesis CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 24332717 t In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities SIGNOR-267194 0.8 SIGNOR-NM Nucleotide Biosynthesis IMPDH2 protein P12268 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267335 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSS2 protein P30520 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267349 0.8 SIGNOR-NM Nucleotide Biosynthesis SAICAR(4-) smallmolecule CHEBI:58443 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-268068 0.8 SIGNOR-NM Nucleotide Biosynthesis DHODH protein Q02127 UNIPROT ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267432 0.8 SIGNOR-NM Nucleotide Biosynthesis MAPK1 protein P28482 UNIPROT PFAS protein O15067 UNIPROT up-regulates phosphorylation Thr619 GQGDAPPtPLPTPVD 9606 32485148 t miannu T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation. SIGNOR-267306 0.2 SIGNOR-NM Nucleotide Biosynthesis L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267529 0.8 SIGNOR-NM Nucleotide Biosynthesis fumarate(2-) smallmolecule CHEBI:29806 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 30090811 f miannu Fumarase is a TCA cycle enzyme which catalyzes the conversion of fumarate to L-malate in the mitochondria. Upon DNA damage the cytosolic echoform of fumarase is localized to the nucleus, there, its enzymatic activity catalyzes the reverse conversion of malate to fumarate, so causing local accumulation of fumarate. SIGNOR-267989 0.7 SIGNOR-NM Nucleotide Biosynthesis coenzyme Q10 smallmolecule CHEBI:46245 ChEBI ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity precursor of 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267429 0.8 SIGNOR-NM Nucleotide Biosynthesis Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267844 0.8 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. SIGNOR-267377 0.301 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267416 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSS2 protein P30520 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267347 0.8 SIGNOR-NM Nucleotide Biosynthesis GART protein P22102 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267315 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267296 0.8 SIGNOR-NM Nucleotide Biosynthesis SAICAR(4-) smallmolecule CHEBI:58443 ChEBI 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266609 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267189 0.8 SIGNOR-NM Nucleotide Biosynthesis PPAT protein Q06203 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267294 0.8 SIGNOR-NM Nucleotide Biosynthesis GMPS protein P49915 UNIPROT L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267341 0.8 SIGNOR-NM Nucleotide Biosynthesis 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267336 0.8 SIGNOR-NM Nucleotide Biosynthesis GMPS protein P49915 UNIPROT guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267338 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSS1 protein Q8N142 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267348 0.8 SIGNOR-NM Nucleotide Biosynthesis PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267318 0.8 SIGNOR-NM Nucleotide Biosynthesis L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267423 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-268096 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267339 0.8 SIGNOR-NM Nucleotide Biosynthesis CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267425 0.8 SIGNOR-NM Nucleotide Biosynthesis 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-268095 0.8 SIGNOR-NM Nucleotide Biosynthesis IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267333 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSL protein P30566 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266606 0.8 SIGNOR-NM Nucleotide Biosynthesis PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed‚Äù SIGNOR-267190 0.8 SIGNOR-NM Nucleotide Biosynthesis RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0002181 23429703 t miannu CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth. SIGNOR-267443 0.386 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT IMPDH1 protein P20839 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. SIGNOR-267378 0.246 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT NFE2L2 factor protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267363 0.539 SIGNOR-NM Nucleotide Biosynthesis 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267324 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266608 0.8 SIGNOR-NM Nucleotide Biosynthesis hydrogencarbonate smallmolecule CHEBI:17544 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267417 0.8 SIGNOR-NM Nucleotide Biosynthesis glycine extracellular smallmolecule CHEBI:15428 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267297 0.8 SIGNOR-NM Nucleotide Biosynthesis MYC factor protein P01106 UNIPROT DHODH protein Q02127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. SIGNOR-267382 0.358 SIGNOR-NM Nucleotide Biosynthesis IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267330 0.8 SIGNOR-NM Nucleotide Biosynthesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-NM Nucleotide Biosynthesis UMPS protein P11172 UNIPROT orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267438 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266907 0.8 SIGNOR-NM Nucleotide Biosynthesis MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 BTO:0000150 19085255 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase. SIGNOR-182808 0.574 SIGNOR-NM Nucleotide Biosynthesis ADSL protein P30566 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression 9606 31729379 f miannu An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels SIGNOR-266614 0.2 SIGNOR-NM Nucleotide Biosynthesis ATP smallmolecule CHEBI:15422 ChEBI 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity precursor of 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267842 0.8 SIGNOR-NM Nucleotide Biosynthesis RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis. SIGNOR-201117 0.386 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267530 0.8 SIGNOR-NM Nucleotide Biosynthesis N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268103 0.8 SIGNOR-NM Nucleotide Biosynthesis N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266610 0.8 SIGNOR-NM Nucleotide Biosynthesis N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-268091 0.8 SIGNOR-NM Nucleotide Biosynthesis IMP smallmolecule CHEBI:17202 ChEBI GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity precursor of 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-268130 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267814 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSL protein P30566 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266607 0.8 SIGNOR-NM Nucleotide Biosynthesis L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) extracellular smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266906 0.8 SIGNOR-NM Nucleotide Biosynthesis MAPK1 protein P28482 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 t lperfetto Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62. SIGNOR-235700 0.725 SIGNOR-NM Nucleotide Biosynthesis ADK protein P55263 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267840 0.8 SIGNOR-NM Nucleotide Biosynthesis ATIC protein P31939 UNIPROT 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267327 0.8 SIGNOR-NM Nucleotide Biosynthesis GART protein P22102 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267305 0.8 SIGNOR-NM Nucleotide Biosynthesis ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-NM Nucleotide Biosynthesis N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268102 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity precursor of 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267292 0.8 SIGNOR-NM Nucleotide Biosynthesis MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol SIGNOR-137171 0.392 SIGNOR-NM Nucleotide Biosynthesis orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267439 0.8 SIGNOR-NM Nucleotide Biosynthesis carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267422 0.8 SIGNOR-NM Nucleotide Biosynthesis ADK protein P55263 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267841 0.8 SIGNOR-NM Nucleotide Biosynthesis IMPDH1 protein P20839 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267332 0.8 SIGNOR-NM Nucleotide Biosynthesis adenosine smallmolecule CHEBI:16335 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 18957298 t miannu Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP. SIGNOR-265465 0.8 SIGNOR-NM Nucleotide Biosynthesis DHODH protein Q02127 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267433 0.8 SIGNOR-NM Nucleotide Biosynthesis adenosine smallmolecule CHEBI:16335 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267836 0.8 SIGNOR-NM Nucleotide Biosynthesis N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-268067 0.8 SIGNOR-NM Nucleotide Biosynthesis ADSS1 protein Q8N142 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267350 0.8 SIGNOR-NM Nucleotide Biosynthesis 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267323 0.8 SIGNOR-NM Nucleotide Biosynthesis ATP smallmolecule CHEBI:15422 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267837 0.8 SIGNOR-NOTCH NOTCH Signaling DLL4 receptor protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 10837024 t lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology SIGNOR-77973 0.624 SIGNOR-NOTCH NOTCH Signaling MYOD1 factor protein P15172 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 f andrea cerquone perpetuini Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation. SIGNOR-255417 0.7 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR Quiescence phenotypesList phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 f gcesareni Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury. SIGNOR-244004 0.7 SIGNOR-NOTCH NOTCH Signaling DLK1 receptor protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-172830 0.493 SIGNOR-NOTCH NOTCH Signaling MIB1 protein Q86YT6 UNIPROT DLL1 extracellular protein O00548 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209750 0.728 SIGNOR-NOTCH NOTCH Signaling HES1 factor protein Q14469 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 t lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-209756 0.673 SIGNOR-NOTCH NOTCH Signaling MIB1 protein Q86YT6 UNIPROT DLL3 receptor protein Q9NYJ7 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209672 0.358 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway. SIGNOR-113786 0.424 SIGNOR-NOTCH NOTCH Signaling JAG2 receptor protein Q9Y219 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 9315665 t gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. SIGNOR-236922 0.603 SIGNOR-NOTCH NOTCH Signaling KDM5A protein P29375 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR down-regulates binding 7227 BTO:0000782 20231316 t lperfetto In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro. SIGNOR-219250 0.395 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT NFKB1 factor protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11591772 f lperfetto Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab. SIGNOR-110963 0.385 SIGNOR-NOTCH NOTCH Signaling HES1 factor protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000970 20208568 f gcesareni The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1. SIGNOR-164071 0.321 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 f lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. SIGNOR-183507 0.764 SIGNOR-NOTCH NOTCH Signaling ADAM17 receptor protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-78903 0.728 SIGNOR-NOTCH NOTCH Signaling JAG1 receptor protein P78504 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 7227 18660822 t Binding Ca-dependent lperfetto We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner. SIGNOR-219253 0.622 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 f flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages SIGNOR-241998 0.7 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f lperfetto Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). SIGNOR-149777 0.2 SIGNOR-NOTCH NOTCH Signaling DLL1 extracellular protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 0.606 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 t lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 0.673 SIGNOR-NOTCH NOTCH Signaling JAG2 receptor protein Q9Y219 UNIPROT JAG1 receptor protein P78504 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 9315665 f gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. SIGNOR-236888 0.382 SIGNOR-NOTCH NOTCH Signaling DLL4 receptor protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 11739188 t lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology SIGNOR-112649 0.624 SIGNOR-NOTCH NOTCH Signaling MIB1 protein Q86YT6 UNIPROT DLL4 receptor protein Q9NR61 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209626 0.528 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 t Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-254381 0.949 SIGNOR-NOTCH NOTCH Signaling DLL3 receptor protein Q9NYJ7 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209738 0.467 SIGNOR-NOTCH NOTCH Signaling DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000165 11226752 t gcesareni Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis SIGNOR-236870 0.772 SIGNOR-NOTCH NOTCH Signaling gamma-secretase receptor complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 0.665 SIGNOR-NOTCH NOTCH Signaling YY1 factor protein P25490 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 9606 BTO:0000664 12913000 t Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. SIGNOR-251654 0.604 SIGNOR-NOTCH NOTCH Signaling MIB1 protein Q86YT6 UNIPROT JAG1 receptor protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000938 12530964 t lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. SIGNOR-97388 0.677 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR HIF1A factor protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19808903 t lperfetto We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene. SIGNOR-209720 0.454 SIGNOR-NOTCH NOTCH Signaling VEGFA extracellular protein P15692 UNIPROT Angiogenesis phenotypesList phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252275 0.7 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR HEY1 factor protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 t lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. SIGNOR-170854 0.706 SIGNOR-NOTCH NOTCH Signaling DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-219269 0.772 SIGNOR-NOTCH NOTCH Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR MYOD1 factor protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000165 10066785 t lperfetto Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis SIGNOR-219359 0.433 SIGNOR-NOTCH NOTCH Signaling NOTCH1 protein P46531 UNIPROT HIF1A factor protein Q16665 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 16256737 t lperfetto The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions. SIGNOR-141315 0.632 SIGNOR-NOTCH NOTCH Signaling DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 9606 11153911 t gcesareni The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway. SIGNOR-85942 0.772 SIGNOR-NOTCH NOTCH Signaling DLL4 receptor protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209735 0.624 SIGNOR-NOTCH NOTCH Signaling HIF1A factor protein Q16665 UNIPROT VEGFA extracellular protein P15692 UNIPROT up-regulates quantity transcriptional regulation 9606 8387214 t Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. SIGNOR-256592 0.767 SIGNOR-NOTCH NOTCH Signaling NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 t lperfetto Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd. SIGNOR-219228 0.424 SIGNOR-NOTCH NOTCH Signaling HES1 factor protein Q14469 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna. SIGNOR-235596 0.3 SIGNOR-NOTCH NOTCH Signaling MIB1 protein Q86YT6 UNIPROT JAG1 receptor protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001253 18043734 t lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. SIGNOR-159480 0.677 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 t gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. SIGNOR-236867 0.797 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 20626350 t lperfetto The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation SIGNOR-166571 0.797 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t The effect has been demonstrated using Q06413-3 lperfetto We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation. SIGNOR-47136 0.68 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT ADAM17 receptor protein P78536 UNIPROT up-regulates activity phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 t gcesareni We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding SIGNOR-163970 0.421 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR MYOD1 factor protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000165 10066785 t lperfetto Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis SIGNOR-219359 0.433 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62788 0.68 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis gamma-secretase receptor complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. SIGNOR-209717 0.665 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HEY1 factor protein Q9Y5J3 UNIPROT MEF2C factor protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19917614 f lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. SIGNOR-235819 0.316 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DLL1 extracellular protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 0.606 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis PAX7 factor protein P23759 UNIPROT Quiescence phenotypesList phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 f svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 f apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 9606 11153911 t gcesareni The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway. SIGNOR-85942 0.772 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12682059 t lperfetto Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain SIGNOR-99762 0.791 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 t Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-254381 0.949 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates activity binding 9606 BTO:0000007 11062068 t gcesareni Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase. SIGNOR-83752 0.797 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 t Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 0.432 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 f Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-219269 0.772 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis PAX7 factor protein P23759 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 f Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 0.624 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR PAX7 factor protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103;BTO:0002314 22493066 t lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene. SIGNOR-219365 0.39 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000165 11226752 t gcesareni Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis SIGNOR-236870 0.772 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR PAX7 factor protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 22493066 f svumbaca Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region. SIGNOR-255365 0.39 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOG factor protein P15173 UNIPROT PAX7 factor protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 f Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions SIGNOR-255638 0.513 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis ADAM17 receptor protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-78903 0.728 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis PAX7 factor protein P23759 UNIPROT Quiescence phenotypesList phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 15843801 f gcesareni We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers. SIGNOR-135626 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HES1 factor protein Q14469 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000165 10066785 t gcesareni Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA SIGNOR-243181 0.3 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HES1 factor protein Q14469 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna. SIGNOR-235596 0.3 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NOTCH1 protein P46531 UNIPROT HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 f lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. SIGNOR-183507 0.764 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MEF2C factor protein Q06413 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 10082551 f lperfetto During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen SIGNOR-219368 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 0.432 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 t lperfetto Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd. SIGNOR-219228 0.424 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MEF2C factor protein Q06413 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 0.733 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR HEY1 factor protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 t lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. SIGNOR-170854 0.706 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f lperfetto Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). SIGNOR-149777 0.2 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOG factor protein P15173 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates transcriptional regulation 9606 SIGNOR-C92 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151694 0.2 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HES1 factor protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000970 20208568 f gcesareni The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1. SIGNOR-164071 0.321 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62796 0.68 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis PAX7 factor protein P23759 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219371 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis NOTCH1 protein P46531 UNIPROT PAX7 factor protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219374 0.406 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis PAX7 factor protein P23759 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 f lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181624 0.624 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 17158101 f Andrea Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis SIGNOR-255744 0.28 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DLK1 receptor protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-172830 0.493 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HES1 factor protein Q14469 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 t lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. SIGNOR-209756 0.673 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway. SIGNOR-113786 0.424 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 15466486 f lperfetto Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii. SIGNOR-129702 0.459 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 f gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235009 0.432 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 t gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. SIGNOR-93873 0.797 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis HEY1 factor protein Q9Y5J3 UNIPROT MYOG factor protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 f lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. SIGNOR-235822 0.382 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR Quiescence phenotypesList phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 f gcesareni Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury. SIGNOR-244004 0.7 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62792 0.68 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47. SIGNOR-176551 0.68 SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 t Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 0.432 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML CDKN2A protein Q8N726 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 f apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes SIGNOR-255694 0.782 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML MEIS1 factor protein O00470 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 f irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. SIGNOR-255859 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML NPM1 protein P06748 UNIPROT HOXA9 factor protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 t miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. SIGNOR-260138 0.363 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-255682 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FLT3 receptor protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.448 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML ETV6 factor protein P41212 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML SOX4 factor protein Q06945 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. SIGNOR-260133 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML DNMT3A protein Q9Y6K1 UNIPROT MEIS1 factor protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 f miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. SIGNOR-256125 0.338 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML GSK3B protein P49841 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc SIGNOR-118844 0.709 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 f Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression SIGNOR-254302 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML DNMT3A protein Q9Y6K1 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 f irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255808 0.483 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML MEIS1 factor protein O00470 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255865 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML CEBPA factor protein P49715 UNIPROT SOX4 factor protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.396 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML STAT5A factor protein P42229 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 f miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. SIGNOR-256233 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 30552988 f miannu Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. SIGNOR-260132 0.298 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. SIGNOR-243545 0.754 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. SIGNOR-244610 0.2 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML FLT3 receptor protein P36888 UNIPROT STAT5A factor protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 SIGNOR-245069 0.594 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML CEBPA factor protein P49715 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML CCND1 factor protein P24385 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. SIGNOR-260014 0.7 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML HOXA9 factor protein P31269 UNIPROT MEIS1 factor protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.647 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 factor protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML GSK3B protein P49841 UNIPROT CCND1 factor protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 t gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. SIGNOR-144818 0.775 SIGNOR-NPM1_new NPM1_new AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 t We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo SIGNOR-256135 0.2 SIGNOR-NPM1_new NPM1_new NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 t gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division SIGNOR-245073 0.575 SIGNOR-NPM1_new NPM1_new BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-NPM1_new NPM1_new IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253135 0.8 SIGNOR-NPM1_new NPM1_new FLT3 receptor protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 t gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. SIGNOR-245057 0.545 SIGNOR-NPM1_new NPM1_new IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 t miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. SIGNOR-253134 0.8 SIGNOR-NPM1_new NPM1_new CEBPA factor protein P49715 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 SIGNOR-NPM1_new NPM1_new 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 t irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. SIGNOR-255706 0.8 SIGNOR-NPM1_new NPM1_new FLT3 receptor protein P36888 UNIPROT CEBPA factor protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.624 SIGNOR-NPM1_new NPM1_new MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-NPM1_new NPM1_new AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001412 31900833 t miannu Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. SIGNOR-260097 0.2 SIGNOR-NPM1_new NPM1_new MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-NPM1_new NPM1_new NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 t gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 SIGNOR-245084 0.498 SIGNOR-NPM1_new NPM1_new NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-NPM1_new NPM1_new TET2 protein Q6N021 UNIPROT WT1 factor protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.467 SIGNOR-NPM1_new NPM1_new AMPK complex SIGNOR-C15 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252880 0.396 SIGNOR-NPM1_new NPM1_new PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. SIGNOR-255754 0.661 SIGNOR-NPM1_new NPM1_new FBXW7 protein Q969H0 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.754 SIGNOR-NPM1_new NPM1_new TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-NPM1_new NPM1_new FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252938 0.7 SIGNOR-NPM1_new NPM1_new MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-NPM1_new NPM1_new AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-NPM1_new NPM1_new RAD21 protein O60216 UNIPROT RUNX1 factor protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 t miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells SIGNOR-259973 0.29 SIGNOR-NPM1_new NPM1_new MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-NPM1_new NPM1_new FLT3 receptor protein P36888 UNIPROT RUNX1 factor protein Q01196 UNIPROT up-regulates activity 9606 28213513 f Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential, SIGNOR-256307 0.375 SIGNOR-NPM1_new NPM1_new MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-NPM1_new NPM1_new CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 t fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. SIGNOR-192697 0.757 SIGNOR-NPM1_new NPM1_new BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-NPM1_new NPM1_new AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-NPM1_new NPM1_new FOXO factor proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260088 0.2 SIGNOR-NPM1_new NPM1_new CEBPA factor protein P49715 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 f miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. SIGNOR-253830 0.506 SIGNOR-NPM1_new NPM1_new CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-NPM1_new NPM1_new TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-NPM1_new NPM1_new ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-NPM1_new NPM1_new RUNX1 factor protein Q01196 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. SIGNOR-249631 0.7 SIGNOR-NPM1_new NPM1_new MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-NPM1_new NPM1_new RUNX1 factor protein Q01196 UNIPROT MYC factor protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 t miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements SIGNOR-260093 0.345 SIGNOR-NPM1_new NPM1_new WT1 factor protein P19544 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. SIGNOR-255705 0.7 SIGNOR-NPM1_new NPM1_new TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-NPM1_new NPM1_new ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. SIGNOR-244505 0.2 SIGNOR-NPM1_new NPM1_new TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-NR Neurotransmitters release DNM1 protein Q05193 UNIPROT SYP protein P08247 UNIPROT up-regulates activity binding 9606 10823955 t miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. SIGNOR-264119 0.343 SIGNOR-NR Neurotransmitters release calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 t It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255491 0.8 SIGNOR-NR Neurotransmitters release UNC13B protein O14795 UNIPROT SNARE_complex receptor complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263972 0.707 SIGNOR-NR Neurotransmitters release STX1A receptor protein Q16623 UNIPROT SNARE_complex receptor complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263968 0.929 SIGNOR-NR Neurotransmitters release SNCA extracellular protein P37840 UNIPROT VAMP2 receptor protein P63027 UNIPROT down-regulates quantity binding 9606 BTO:0000938 31110017 t miannu The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering. SIGNOR-264104 0.413 SIGNOR-NR Neurotransmitters release ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-NR Neurotransmitters release ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-NR Neurotransmitters release STON2 protein Q8WXE9 UNIPROT VAMP2 receptor protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. SIGNOR-264113 0.543 SIGNOR-NR Neurotransmitters release PKA proteinfamily SIGNOR-PF17 SIGNOR SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 t miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation SIGNOR-264108 0.2 SIGNOR-NR Neurotransmitters release DNM1 protein Q05193 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 10823955 f miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. SIGNOR-264118 0.7 SIGNOR-NR Neurotransmitters release CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, SIGNOR-103886 0.354 SIGNOR-NR Neurotransmitters release SYBU protein Q9NX95 UNIPROT STX1A receptor protein Q16623 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264812 0.438 SIGNOR-NR Neurotransmitters release SNAP25 receptor protein P60880 UNIPROT SNARE_complex receptor complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263967 0.957 SIGNOR-NR Neurotransmitters release calcium(2+) smallmolecule CHEBI:29108 ChEBI SYT1 protein P21579 UNIPROT up-regulates activity chemical activation 9606 16679567 t miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion SIGNOR-263976 0.8 SIGNOR-NR Neurotransmitters release SYN1 protein P17600 UNIPROT Synaptic_vesicle_exocytosis extracellular phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. SIGNOR-264105 0.7 SIGNOR-NR Neurotransmitters release APBA1 protein Q02410 UNIPROT NRXN1 receptor protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 t miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. SIGNOR-264038 0.651 SIGNOR-NR Neurotransmitters release GPCR receptor proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t miannu Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-255006 0.2 SIGNOR-NR Neurotransmitters release calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis extracellular phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 11988172 f miannu Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. SIGNOR-264355 0.7 SIGNOR-NR Neurotransmitters release SCRIB protein Q14160 UNIPROT Synaptic_vesicle_exocytosis extracellular phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 19458197 f miannu Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses. SIGNOR-265827 0.7 SIGNOR-NR Neurotransmitters release SYT1 protein P21579 UNIPROT SNAP25 receptor protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 t miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion SIGNOR-263975 0.948 SIGNOR-NR Neurotransmitters release VAMP2 receptor protein P63027 UNIPROT SNARE_complex receptor complex SIGNOR-C346 SIGNOR form complex binding 9606 30267828 t miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-263966 0.931 SIGNOR-NR Neurotransmitters release RIMS1 protein Q86UR5 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264385 0.792 SIGNOR-NR Neurotransmitters release RAB3A protein P20336 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 f miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  SIGNOR-264375 0.7 SIGNOR-NR Neurotransmitters release GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 15922020 t Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. SIGNOR-256532 0.53 SIGNOR-NR Neurotransmitters release SYP protein P08247 UNIPROT VAMP2 receptor protein P63027 UNIPROT up-regulates quantity binding 9606 17331077 t miannu Synaptophysin I interacts with VAMP2 and controls its subcellular distribution. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. This model implicates synaptophysin I in escorting VAMP2 to the sites where exocytosis must take place exclusively after the arrival of the appropriate stimulus. We show that, at early stages along the secretory pathway, synaptophysin I directs sorting of VAMP2 to vesicles exhibiting limited availability for constitutive exocytosis. SIGNOR-264102 0.625 SIGNOR-NR Neurotransmitters release 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-NR Neurotransmitters release SNARE_complex receptor complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis extracellular phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-265065 0.7 SIGNOR-NR Neurotransmitters release SV2A protein Q7L0J3 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. SIGNOR-264116 0.558 SIGNOR-NR Neurotransmitters release STON2 protein Q8WXE9 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. SIGNOR-264115 0.77 SIGNOR-NR Neurotransmitters release CSNK2A1 protein P68400 UNIPROT STX1A receptor protein Q16623 UNIPROT up-regulates phosphorylation Ser14 ELRTAKDsDDDDDVA 9606 11846792 t lperfetto In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin SIGNOR-114840 0.374 SIGNOR-NR Neurotransmitters release STXBP1 protein P61764 UNIPROT STX1A receptor protein Q16623 UNIPROT up-regulates activity binding 10116 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264042 0.919 SIGNOR-NR Neurotransmitters release RIMS1 protein Q86UR5 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264381 0.799 SIGNOR-NR Neurotransmitters release SNX9 protein Q9Y5X1 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. SIGNOR-133892 0.78 SIGNOR-NR Neurotransmitters release APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 9395480 t miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. SIGNOR-264035 0.688 SIGNOR-NR Neurotransmitters release CACNA1A receptor protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264323 0.8 SIGNOR-NR Neurotransmitters release CSNK2A1 protein P68400 UNIPROT SNCA extracellular protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes. SIGNOR-73807 0.486 SIGNOR-NR Neurotransmitters release CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT up-regulates activity binding 9606 BTO:0000938 21255999 t miannu Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs. SIGNOR-265826 0.431 SIGNOR-NR Neurotransmitters release DAPK1 protein P53355 UNIPROT STX1A receptor protein Q16623 UNIPROT down-regulates activity phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 t llicata Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. SIGNOR-251083 0.345 SIGNOR-NR Neurotransmitters release SYP protein P08247 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 33769286 f miannu This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII. SIGNOR-264111 0.7 SIGNOR-NR Neurotransmitters release Cadherins receptor proteinfamily SIGNOR-PF71 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265812 0.2 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation SIGNOR-252081 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236471 0.2 SIGNOR-NS Noonan syndrome NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 t Translocation from Cytosol to Membrane gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175231 0.864 SIGNOR-NS Noonan syndrome GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236516 0.2 SIGNOR-NS Noonan syndrome GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-NS Noonan syndrome BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-NS Noonan syndrome SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 t gcesareni Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway. SIGNOR-110948 0.397 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.769 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235956 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites SIGNOR-235738 0.921 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT SPRY1 protein O43609 UNIPROT down-regulates dephosphorylation 9606 16481357 t gcesareni These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor. SIGNOR-144547 0.422 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236412 0.749 SIGNOR-NS Noonan syndrome SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236363 0.761 SIGNOR-NS Noonan syndrome MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.743 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244747 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236420 0.749 SIGNOR-NS Noonan syndrome MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236262 0.951 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236475 0.2 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 t Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, SIGNOR-248666 0.865 SIGNOR-NS Noonan syndrome KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.84 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236392 0.749 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236408 0.749 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236467 0.2 SIGNOR-NS Noonan syndrome KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 10882715 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-78911 0.84 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248674 0.951 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 t lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175259 0.769 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 SIGNOR-NS Noonan syndrome SHOC2 protein Q9UQ13 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0000007 16630891 t Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site SIGNOR-251647 0.57 SIGNOR-NS Noonan syndrome HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-NS Noonan syndrome NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.848 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252086 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236523 0.2 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-NS Noonan syndrome HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.933 SIGNOR-NS Noonan syndrome HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 t lperfetto We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. SIGNOR-235786 0.933 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235951 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 t lperfetto Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma). SIGNOR-233233 0.749 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr. SIGNOR-235481 0.91 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 24697349 t Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades. SIGNOR-267725 0.921 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236254 0.951 SIGNOR-NS Noonan syndrome BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-NS Noonan syndrome RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000975 11018021 t lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244945 0.733 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233520 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 11350724 t lperfetto Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways. SIGNOR-107712 0.91 SIGNOR-NS Noonan syndrome PPP1CA protein P62136 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases SIGNOR-269927 0.459 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236527 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236479 0.2 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244743 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. SIGNOR-251093 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236396 0.749 SIGNOR-NS Noonan syndrome KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-NS Noonan syndrome GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 t Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. lperfetto The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2 SIGNOR-235917 0.867 SIGNOR-NS Noonan syndrome HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT EGFR receptor protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not SIGNOR-236424 0.865 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236416 0.749 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252083 0.2 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236400 0.749 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252084 0.2 SIGNOR-NS Noonan syndrome RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.733 SIGNOR-NS Noonan syndrome BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-NS Noonan syndrome HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 t lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. SIGNOR-244591 0.2 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 SIGNOR-NS Noonan syndrome BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236258 0.951 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236404 0.749 SIGNOR-NS Noonan syndrome GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-NS Noonan syndrome RIT1 protein Q92963 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 10090 BTO:0000944 23791108 t It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development. SIGNOR-251650 0.526 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236487 0.2 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-NS Noonan syndrome PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 16630891 t We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins SIGNOR-251649 0.274 SIGNOR-NS Noonan syndrome SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236483 0.2 SIGNOR-NS Noonan syndrome PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 11323411 t These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. SIGNOR-248675 0.951 SIGNOR-NS Noonan syndrome EGFR receptor protein P00533 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236531 0.2 SIGNOR-NS Noonan syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252082 0.2 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-252672 0.772 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) TP53 factor protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni P53 interacts with the pro-apoptotic mitochondrial membrane protein bak SIGNOR-124122 0.676 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) TP53 factor protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 t Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis SIGNOR-99712 0.738 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) IGF1R receptor protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-252690 0.685 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR TP53 factor protein P04637 UNIPROT up-regulates quantity 9606 19879762 f lperfetto In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus. SIGNOR-209690 0.7 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) TGFA extracellular protein P01135 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.895 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here SIGNOR-249585 0.638 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.921 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim) SIGNOR-55546 0.656 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. SIGNOR-252671 0.772 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 14967450 t miannu All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor SIGNOR-256162 0.2 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256168 0.772 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-OS Oxytocin signaling Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR receptor protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current SIGNOR-16758 0.2 SIGNOR-OS Oxytocin signaling PAM extracellular protein P19021 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 23084901 t lperfetto Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme. SIGNOR-268551 0.2 SIGNOR-OS Oxytocin signaling HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.933 SIGNOR-OS Oxytocin signaling PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 SIGNOR-OS Oxytocin signaling PLCB1 protein Q9NQ66 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256496 0.8 SIGNOR-OS Oxytocin signaling GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152609 0.287 SIGNOR-OS Oxytocin signaling Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268578 0.2 SIGNOR-OS Oxytocin signaling GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-37149 0.76 SIGNOR-OS Oxytocin signaling GNAI1 protein P63096 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 15922020 t miannu Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. SIGNOR-267853 0.614 SIGNOR-OS Oxytocin signaling calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis extracellular phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 11988172 f miannu Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. SIGNOR-264355 0.7 SIGNOR-OS Oxytocin signaling PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 SIGNOR-OS Oxytocin signaling GNAS protein Q5JWF2 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 12145344 t lperfetto HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP SIGNOR-268693 0.729 SIGNOR-OS Oxytocin signaling calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-252320 0.8 SIGNOR-OS Oxytocin signaling RARA factor protein P10276 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268548 0.258 SIGNOR-OS Oxytocin signaling PCSK5 protein Q92824 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270334 0.2 SIGNOR-OS Oxytocin signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-OS Oxytocin signaling GRK2 receptor protein P25098 UNIPROT OXTR receptor protein P30559 UNIPROT down-regulates activity phosphorylation 9534 BTO:0000298 16179383 t miannu Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization SIGNOR-270329 0.2 SIGNOR-OS Oxytocin signaling PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotypesList phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264960 0.7 SIGNOR-OS Oxytocin signaling PCSK2 protein P16519 UNIPROT OXT extracellular protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270328 0.27 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270331 0.404 SIGNOR-OS Oxytocin signaling PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264961 0.7 SIGNOR-OS Oxytocin signaling DRD2 receptor protein P14416 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-264993 0.581 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257065 0.424 SIGNOR-OS Oxytocin signaling CD38 protein P28907 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity relocalization 10090 17287729 f lperfetto CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. SIGNOR-268544 0.379 SIGNOR-OS Oxytocin signaling Calcineurin complex SIGNOR-C155 SIGNOR Chemorepulsion_of_axon phenotypesList phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 15363394 f miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. SIGNOR-268386 0.7 SIGNOR-OS Oxytocin signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 f Luana Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. SIGNOR-264978 0.7 SIGNOR-OS Oxytocin signaling Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 11376933 t miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. SIGNOR-267844 0.8 SIGNOR-OS Oxytocin signaling 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 receptor protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIGNOR-OS Oxytocin signaling calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264953 0.7 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT DRD2 receptor protein P14416 UNIPROT up-regulates activity binding 10116 27425032 t miannu Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. SIGNOR-270333 0.388 SIGNOR-OS Oxytocin signaling ESR1 factor protein P03372 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268546 0.445 SIGNOR-OS Oxytocin signaling GNAQ protein P50148 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 9235901 t gcesareni Galfaq/11 subunits also activate p21ras SIGNOR-50104 0.632 SIGNOR-OS Oxytocin signaling PCSK2 protein P16519 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270337 0.2 SIGNOR-OS Oxytocin signaling PCSK2 protein P16519 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270335 0.2 SIGNOR-OS Oxytocin signaling GNB5 protein O14775 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-267850 0.453 SIGNOR-OS Oxytocin signaling CAPRIN2 protein Q6IMN6 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000007 35051932 t lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. SIGNOR-268556 0.2 SIGNOR-OS Oxytocin signaling RARB factor protein P10826 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268549 0.2 SIGNOR-OS Oxytocin signaling GABA-A receptor proteinfamily SIGNOR-PF61 SIGNOR Excitatory_synaptic_transmission phenotypesList phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264970 0.7 SIGNOR-OS Oxytocin signaling Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR receptor protein P30559 UNIPROT up-regulates activity binding 9606 11274341 t lperfetto The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. SIGNOR-268545 0.2 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270332 0.53 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270330 0.424 SIGNOR-OS Oxytocin signaling CREB1 factor protein P16220 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 f Luana These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation. SIGNOR-265773 0.7 SIGNOR-OS Oxytocin signaling Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity binding 9606 BTO:0000427 9511957 t miannu  Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.  SIGNOR-270351 0.2 SIGNOR-OS Oxytocin signaling TAC1 extracellular protein P20366 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity 35045339 f lperfetto Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions|Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. SIGNOR-268576 0.575 SIGNOR-OS Oxytocin signaling OXTR receptor protein P30559 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256793 0.404 SIGNOR-OS Oxytocin signaling CREB3L1 factor protein Q96BA8 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 35051932 f lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls SIGNOR-268555 0.2 SIGNOR-OS Oxytocin signaling 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-OS Oxytocin signaling PCSK5 protein Q92824 UNIPROT OXT extracellular protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270327 0.252 SIGNOR-OS Oxytocin signaling PLCE1 protein Q9P212 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152771 0.8 SIGNOR-OS Oxytocin signaling RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.733 SIGNOR-OS Oxytocin signaling calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 SIGNOR-OS Oxytocin signaling ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-OS Oxytocin signaling THRA receptor protein P10827 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268550 0.2 SIGNOR-OS Oxytocin signaling PCSK5 protein Q92824 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270336 0.2 SIGNOR-OS Oxytocin signaling ESR2 receptor protein Q92731 UNIPROT OXT extracellular protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268547 0.493 SIGNOR-OS Oxytocin signaling 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 SIGNOR-OS Oxytocin signaling LNPEP protein Q9UIQ6 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT down-regulates quantity by destabilization cleavage 9606 25767437 t miannu It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP) SIGNOR-268552 0.2 SIGNOR-P38 P38 Signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR TP53 factor protein P04637 UNIPROT up-regulates quantity 9606 19879762 f lperfetto In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus. SIGNOR-209690 0.7 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247053 0.2 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250101 0.754 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 t lperfetto Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161763 0.578 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131399 0.2 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131395 0.2 SIGNOR-P38 P38 Signaling PPM1D protein O15297 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-248319 0.582 SIGNOR-P38 P38 Signaling TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 10116 BTO:0003324 16407200 t lperfetto In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization. SIGNOR-143576 0.818 SIGNOR-P38 P38 Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-P38 P38 Signaling TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates activity phosphorylation Ser79 EVTSTSQsPHSPDSS 9606 8650547 t lperfetto ...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator. SIGNOR-42200 0.59 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 17535811 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-155242 0.764 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 0.728 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 t ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 0.728 SIGNOR-P38 P38 Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.57 SIGNOR-P38 P38 Signaling STAT1 factor protein P42224 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21433395 f miannu The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic. SIGNOR-263651 0.7 SIGNOR-P38 P38 Signaling TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t giulio giuliani In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa) SIGNOR-255960 0.838 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 t lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 0.728 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-P38 P38 Signaling DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 t gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. SIGNOR-93873 0.797 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-131375 0.588 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells. SIGNOR-134329 0.453 SIGNOR-P38 P38 Signaling TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 t lperfetto The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway SIGNOR-60818 0.555 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0003316 10781582 t lperfetto Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo. SIGNOR-226614 0.764 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 0.728 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-130736 0.588 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72699 0.764 SIGNOR-P38 P38 Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 0.71 SIGNOR-P38 P38 Signaling TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 11279118 t lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells SIGNOR-106462 0.649 SIGNOR-P38 P38 Signaling MAPKAPK2 protein P49137 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-153944 0.678 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118036 0.754 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity 9606 9890973 f lperfetto These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. SIGNOR-63979 0.301 SIGNOR-P38 P38 Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.71 SIGNOR-P38 P38 Signaling TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0001130 10660600 t lperfetto Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. SIGNOR-74864 0.264 SIGNOR-P38 P38 Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.864 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.721 SIGNOR-P38 P38 Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 10747897 t miannu We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase SIGNOR-250114 0.764 SIGNOR-P38 P38 Signaling MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 t lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. SIGNOR-62372 0.636 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck SIGNOR-249375 0.597 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251395 0.597 SIGNOR-P38 P38 Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.71 SIGNOR-P38 P38 Signaling TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.838 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function SIGNOR-251393 0.597 SIGNOR-P38 P38 Signaling STAT1 factor protein P42224 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates activity binding 9606 19041276 t lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus SIGNOR-249495 0.2 SIGNOR-P38 P38 Signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 17396146 f lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. SIGNOR-226602 0.7 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158423 0.2 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131387 0.2 SIGNOR-P38 P38 Signaling TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 9774977 t lperfetto Traf2 is a strong activator of ask1 SIGNOR-60747 0.726 SIGNOR-P38 P38 Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-P38 P38 Signaling PTCRA receptor protein Q6ISU1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 20626350 t lperfetto However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck. SIGNOR-166658 0.344 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126 SIGNOR-247044 0.2 SIGNOR-P38 P38 Signaling TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 11847341 t lperfetto Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha. SIGNOR-114843 0.818 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 17535811 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-155246 0.764 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 11258706 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-105741 0.764 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Thr431 ASTLDEAtPTLTNQS 9606 19393267 t lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. SIGNOR-185584 0.818 SIGNOR-P38 P38 Signaling TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.692 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT USF1 factor protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 19389701 t lperfetto Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes SIGNOR-185572 0.531 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-105737 0.764 SIGNOR-P38 P38 Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 0.71 SIGNOR-P38 P38 Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.71 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr25 APPPQPPtPALPHPP 9606 8846784 t lperfetto Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation SIGNOR-44351 0.754 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 8756661 t lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 SIGNOR-43324 0.2 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 t lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 0.2 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236116 0.728 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. SIGNOR-226628 0.597 SIGNOR-P38 P38 Signaling MAPKAPK2 protein P49137 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8887554 t lperfetto We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro. SIGNOR-44384 0.678 SIGNOR-P38 P38 Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain SIGNOR-245029 0.799 SIGNOR-P38 P38 Signaling MAP3K4 protein Q9Y6R4 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity phosphorylation Thr1494 KLKNNAQtMPGEVNS 9606 17242196 t lperfetto Gadd45 binding also induced mtk1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of mtk1 at thr-1493 in the kinase activation loop. SIGNOR-152408 0.2 SIGNOR-P38 P38 Signaling TGFB1 extracellular protein P01137 UNIPROT TGFB1 extracellular protein P01137 UNIPROT up-regulates activity binding 9606 16885528 t lperfetto The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge. SIGNOR-148605 0.2 SIGNOR-P38 P38 Signaling TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.838 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.748 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158427 0.2 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131391 0.2 SIGNOR-P38 P38 Signaling MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251420 0.2 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 t lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. SIGNOR-185580 0.818 SIGNOR-P38 P38 Signaling TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-41941 0.926 SIGNOR-P38 P38 Signaling DDIT3 factor protein P35638 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 SIGNOR-P38 P38 Signaling DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 17396146 f lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. SIGNOR-226599 0.7 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser438 TPTLTNQsPTLTLQS 9606 BTO:0000801 14592977 t lperfetto Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?. SIGNOR-118922 0.818 SIGNOR-P38 P38 Signaling UV stress extracellular stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 f lperfetto Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway SIGNOR-226605 0.7 SIGNOR-P38 P38 Signaling MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50894 0.636 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250102 0.754 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45353 0.592 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227536 0.2 SIGNOR-P38 P38 Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72703 0.764 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45366 0.612 SIGNOR-P38 P38 Signaling MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50891 0.622 SIGNOR-P38 P38 Signaling TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 t gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 0.44 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 16049944 t lperfetto Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493 SIGNOR-139098 0.2 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782 7642520 t lperfetto When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck SIGNOR-30429 0.597 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPT protein P10636 UNIPROT up-regulates phosphorylation 9606 20626350 t lperfetto A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins. SIGNOR-166611 0.325 SIGNOR-P38 P38 Signaling MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251421 0.2 SIGNOR-P38 P38 Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 SIGNOR-27973 0.57 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 8756661 t lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 SIGNOR-226624 0.2 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118040 0.754 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 8974401 t lperfetto ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively SIGNOR-226672 0.578 SIGNOR-P38 P38 Signaling PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 11101524 t lperfetto Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue SIGNOR-84793 0.461 SIGNOR-P38 P38 Signaling MAPKAPK2 protein P49137 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-166619 0.678 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000567 15642743 t lperfetto Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P SIGNOR-226620 0.764 SIGNOR-P38 P38 Signaling TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 10688666 t lperfetto Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide SIGNOR-75334 0.726 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 t lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 0.48 SIGNOR-P38 P38 Signaling TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 17299140 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-153031 0.926 SIGNOR-P38 P38 Signaling TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity binding 9606 10497253 t lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. SIGNOR-70950 0.627 SIGNOR-P38 P38 Signaling DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 20626350 t lperfetto The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation SIGNOR-166571 0.797 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates activity phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 t miannu CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). SIGNOR-250096 0.59 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72695 0.764 SIGNOR-P38 P38 Signaling MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10347227 t lperfetto However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-236122 0.2 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 t lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45373 0.612 SIGNOR-P38 P38 Signaling PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 9707433 t lperfetto Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay SIGNOR-59618 0.418 SIGNOR-P38 P38 Signaling TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 0.44 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-43659 0.597 SIGNOR-P38 P38 Signaling TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells SIGNOR-106465 0.627 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 0.2 SIGNOR-P38 P38 Signaling PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 19713933 t lperfetto In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38. SIGNOR-187770 0.461 SIGNOR-P38 P38 Signaling TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity binding -1 10497253 t lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. SIGNOR-70947 0.649 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 t lperfetto They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4. SIGNOR-81372 0.2 SIGNOR-P38 P38 Signaling CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-P38 P38 Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.748 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131407 0.2 SIGNOR-P38 P38 Signaling RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 BTO:0000130 14499342 t lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. SIGNOR-118044 0.754 SIGNOR-P38 P38 Signaling PPM1D protein O15297 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-135980 0.582 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-67443 0.597 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251392 0.597 SIGNOR-P38 P38 Signaling MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr842 CTETFTGtLQYMAPE 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158431 0.2 SIGNOR-P38 P38 Signaling ROS extracellular stimulus SIGNOR-ST2 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates 9606 11266364 f lperfetto TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1_JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis. SIGNOR-226609 0.7 SIGNOR-P38 P38 Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.864 SIGNOR-P38 P38 Signaling ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247048 0.2 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 0.2 SIGNOR-P38 P38 Signaling TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 17135271 t These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK. SIGNOR-252099 0.2 SIGNOR-P38 P38 Signaling TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 0.838 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-192057 0.764 SIGNOR-P38 P38 Signaling MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227540 0.2 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249199 0.588 SIGNOR-P38 P38 Signaling TRAF6 protein Q9Y4K3 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205455 0.859 SIGNOR-P38 P38 Signaling LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251396 0.597 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 9687510 t lperfetto Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,. SIGNOR-59454 0.588 SIGNOR-P38 P38 Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 t lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 0.864 SIGNOR-P38 P38 Signaling MAPK14 protein Q16539 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t lperfetto All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154779 0.708 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10347227 t lperfetto However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-236122 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0000661 16603398 t lperfetto Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1. SIGNOR-145861 0.855 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT1 protein P31749 UNIPROT EZH2 factor protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-141043 0.62 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t The effect has been demonstrated using Q06413-3 lperfetto We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation. SIGNOR-47136 0.68 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 FGLSRLMtGDTYTAH 9606 10964922 t Manara We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity. SIGNOR-260781 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158423 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT ADAM17 receptor protein P78536 UNIPROT up-regulates activity phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 t gcesareni We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding SIGNOR-163970 0.421 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62788 0.68 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages SIGNOR-256025 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT EZH2 factor protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372 SIGNOR-255663 0.385 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2D factor protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000887 18026121 t lperfetto Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. SIGNOR-159331 0.592 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.71 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TCF3 factor protein P15923 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 1649701 t E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin lperfetto In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators. SIGNOR-20540 0.797 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11781820 t lperfetto Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity. SIGNOR-113659 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 f apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function SIGNOR-255112 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251420 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SPAG9 protein O60271 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235548 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 t lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation SIGNOR-185765 0.501 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 t lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 0.933 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT1 protein P31749 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 t lperfetto Akt phosphorylated sek1 on serine 78. SIGNOR-236494 0.577 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1 extracellular protein P05019 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 0.955 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2A factor protein Q02078 UNIPROT unknown phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0000938 BTO:0000887 12586839 t lperfetto A p38 mapk-induced phosphopeptide with no mapk consensus the phosphorylation site is identified as ser-408 SIGNOR-98224 0.642 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 0.71 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236116 0.728 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235554 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNFRSF1A receptor protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 f [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation SIGNOR-253600 0.384 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.748 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 14732063 t miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253593 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227536 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 t Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 0.432 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 t p38 together with Bnip-2 and CDC42 to activate p38alfa/beta activity lperfetto During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself. SIGNOR-179870 0.474 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251421 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 f Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. SIGNOR-255644 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 t lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45373 0.612 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MEF2A factor protein Q02078 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54086 0.733 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256022 0.528 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 t lperfetto Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages SIGNOR-120268 0.933 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227540 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 t lperfetto Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation. SIGNOR-179861 0.697 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOG factor protein P15173 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 0.933 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26586 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.692 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity binding 9606 BTO:0000222 19470755 t lperfetto Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity SIGNOR-185762 0.489 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT EZH2 factor protein Q15910 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C77 21902831 t lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. SIGNOR-176548 0.385 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNFRSF1A receptor protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253602 0.384 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT2 protein P31751 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation Ser193 GLPERSVsLTGAPES 10116 17177604 t lperfetto AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay. SIGNOR-151220 0.354 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2A factor protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62784 0.642 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 t lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235551 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MEF2C factor protein Q06413 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 10082551 f lperfetto During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen SIGNOR-219368 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. SIGNOR-252497 0.691 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-106593 0.502 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci. SIGNOR-176557 0.377 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158427 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 0.432 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t lperfetto In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. SIGNOR-150282 0.474 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2A factor protein Q02078 UNIPROT unknown phosphorylation Ser453 PRQEMGRsPVDSLSS 9606 BTO:0000938 BTO:0000887 12586839 t lperfetto Thr-312 and thr-319 are known phosphorylation sites important for the increased transcriptional activation of mef2a by p38 mapk. Ser-453 and ser-479 are phosphorylated in vitro but were not important functionally SIGNOR-98228 0.642 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45353 0.592 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT TCF3 factor protein P15923 UNIPROT up-regulates activity phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t lperfetto Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription SIGNOR-134194 0.455 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2A factor protein Q02078 UNIPROT up-regulates activity phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62780 0.642 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45366 0.612 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP lperfetto Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. SIGNOR-149979 0.537 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDC42 protein P60953 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 21902831 f lperfetto Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation. SIGNOR-176501 0.584 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MEF2C factor protein Q06413 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 0.733 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 SIGNOR-27973 0.57 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 8974401 t lperfetto ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively SIGNOR-226672 0.578 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 15327770 t lperfetto TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2. SIGNOR-128406 0.855 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery SIGNOR-235856 0.554 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 t lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 0.48 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOG factor protein P15173 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates transcriptional regulation 9606 SIGNOR-C92 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151694 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT2 protein P31751 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 f lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 SIGNOR-100591 0.411 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62796 0.68 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis ADAM17 receptor protein P78536 UNIPROT TNF extracellular protein P01375 UNIPROT up-regulates quantity cleavage 9606 BTO:0000782 9034190 t lperfetto We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified. SIGNOR-46754 0.692 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.748 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246252 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235545 0.364 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr842 CTETFTGtLQYMAPE 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158431 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1 extracellular protein P05019 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity binding 9606 21798082 t lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 0.955 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 15870273 t lperfetto This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion SIGNOR-136130 0.56 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SMARCD3 protein Q6STE5 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins. SIGNOR-136945 0.364 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 17151142 t miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNFRSF1A receptor protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38. SIGNOR-235370 0.384 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 t Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 0.432 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis ABL1 protein P00519 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates activity phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 t We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage. SIGNOR-253055 0.292 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.71 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 t ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. SIGNOR-255780 0.728 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 f gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235009 0.432 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2D factor protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Through phosphorylation of mef2d, p38 recruits an ash2l-containing complex to myogenic loci during differentiation, which results in the marking of these genes for expression. SIGNOR-176554 0.592 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 t lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 0.728 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.71 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDH15 receptor protein P55291 UNIPROT CDON receptor protein Q4KMG0 UNIPROT up-regulates activity binding 9606 12634428 t lperfetto Cdo binds promyogenic cadherins form complexes with n- and m-cadherin. SIGNOR-99250 0.471 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 10090 11715022 f lperfetto We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. SIGNOR-235373 0.401 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 0.728 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 12181443 f lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. SIGNOR-91408 0.411 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62792 0.68 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNFRSF1A receptor protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f lperfetto Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. SIGNOR-226637 0.384 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis EZH2 factor protein Q15910 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR down-regulates activity 10090 15520282 f We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts SIGNOR-255719 0.7 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 0.71 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT1 protein P31749 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-217670 0.597 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis SMARCD3 protein Q6STE5 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding -1 22068056 t lperfetto We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes. SIGNOR-238289 0.56 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 0.728 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 t lperfetto Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence. SIGNOR-39142 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.57 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 t lperfetto Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity SIGNOR-100588 0.627 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. SIGNOR-252465 0.712 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT MEF2C factor protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47. SIGNOR-176551 0.68 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity 9606 20626350 f lperfetto On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment. SIGNOR-166591 0.411 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 0.2 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis AKT2 protein P31751 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 t lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-217673 0.308 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 t lperfetto Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161763 0.578 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis CDON receptor protein Q4KMG0 UNIPROT BNIP2 protein Q12982 UNIPROT up-regulates activity binding 9606 18678706 t lperfetto Bnip-2 and jlp are brought together through mutual interaction with cdo. the cdo-bnip-2 interaction stimulates cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation. SIGNOR-179864 0.483 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-PC Prostate Cancer PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-209856 0.724 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 t lperfetto The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor SIGNOR-244140 0.2 SIGNOR-PC Prostate Cancer TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-257606 0.7 SIGNOR-PC Prostate Cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 0.7 SIGNOR-PC Prostate Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-PC Prostate Cancer SPOP protein O43791 UNIPROT NCOA3 factor protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 24239470 t miannu Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems. SIGNOR-251529 0.496 SIGNOR-PC Prostate Cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-PC Prostate Cancer ERG protein P11308 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251554 0.288 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 SIGNOR-244136 0.2 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-PC Prostate Cancer NKX3-1 factor protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates activity binding 9606 16697957 t miannu NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. SIGNOR-251549 0.377 SIGNOR-PC Prostate Cancer NKX3-1 factor protein Q99801 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization 9606 16697957 f miannu NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex SIGNOR-251548 0.368 SIGNOR-PC Prostate Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251539 0.7 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251540 0.7 SIGNOR-PC Prostate Cancer NKX3-1 factor protein Q99801 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 16697957 t miannu NKX3.1 negatively regulates AKT activity in an AR-dependent manner SIGNOR-251552 0.501 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 factor protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 t lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 SIGNOR-244259 0.2 SIGNOR-PC Prostate Cancer PPARG factor protein P37231 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates relocalization 9606 16431920 t fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome SIGNOR-143961 0.596 SIGNOR-PC Prostate Cancer UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotypesList phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 f miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. SIGNOR-251544 0.7 SIGNOR-PC Prostate Cancer NCOA2 factor protein Q15596 UNIPROT PPARG factor protein P37231 UNIPROT up-regulates binding 9606 18584035 t gcesareni Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction. SIGNOR-179175 0.754 SIGNOR-PC Prostate Cancer TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-PC Prostate Cancer EZH2 factor protein Q15910 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 23239736 t miannu This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors). SIGNOR-251542 0.562 SIGNOR-PC Prostate Cancer NCOA2 factor protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 t miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis SIGNOR-251531 0.896 SIGNOR-PC Prostate Cancer TMPRSS2 receptor protein O15393 UNIPROT HGF extracellular protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25122198 t miannu we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program. SIGNOR-263657 0.2 SIGNOR-PC Prostate Cancer PPARG factor protein P37231 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity 9606 23128507 t PAX8-PPARγ fusion protein miannu The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway. SIGNOR-251997 0.476 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-PC Prostate Cancer MET receptor protein P08581 UNIPROT Metastasis phenotypesList phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases. SIGNOR-263658 0.7 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation SIGNOR-254353 0.7 SIGNOR-PC Prostate Cancer PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.812 SIGNOR-PC Prostate Cancer PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-PC Prostate Cancer PIK3CA protein P42336 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 SIGNOR-PC Prostate Cancer HGF extracellular protein P14210 UNIPROT MET receptor protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene. SIGNOR-38429 0.927 SIGNOR-PC Prostate Cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. SIGNOR-244396 0.73 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19632176 t miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. SIGNOR-251543 0.412 SIGNOR-PC Prostate Cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-PC Prostate Cancer PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001332 19903340 f lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression SIGNOR-244439 0.662 SIGNOR-PC Prostate Cancer PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001271 20596030 f lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166478 0.662 SIGNOR-PC Prostate Cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259110 0.7 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT TMPRSS2 receptor protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24505269 t miannu Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma. SIGNOR-251545 0.601 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT Differentiation phenotypesList phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251538 0.7 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254952 0.7 SIGNOR-PC Prostate Cancer ERG protein P11308 UNIPROT EZH2 factor protein Q15910 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251555 0.351 SIGNOR-PC Prostate Cancer NKX3-1 factor protein Q99801 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251547 0.525 SIGNOR-PC Prostate Cancer NCOA2 factor protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 t miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis SIGNOR-251530 0.896 SIGNOR-PC Prostate Cancer FOXA1 factor protein P55317 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24875621 t miannu FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC SIGNOR-251541 0.758 SIGNOR-PC Prostate Cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-PC Prostate Cancer AR protein P10275 UNIPROT NKX3-1 factor protein Q99801 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16697957 t miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. SIGNOR-251546 0.525 SIGNOR-PC Prostate Cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-PC Prostate Cancer PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.812 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 t miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. SIGNOR-151138 0.839 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 t lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. SIGNOR-107256 0.747 SIGNOR-PCP p53 in cancer CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245480 0.7 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 t lperfetto In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158632 0.839 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75025 0.785 SIGNOR-PCP p53 in cancer BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 t lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. SIGNOR-249612 0.615 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115340 0.839 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75637 0.785 SIGNOR-PCP p53 in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 f miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. SIGNOR-253376 0.7 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115344 0.839 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.785 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 t gcesareni DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation SIGNOR-167156 0.839 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.747 SIGNOR-PCP p53 in cancer ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.5 SIGNOR-PCP p53 in cancer RB1 protein P06400 UNIPROT Cell_cycle_block phenotypesList phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-245486 0.7 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.785 SIGNOR-PCP p53 in cancer BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 10629050 t Following Bid-induced conformational change lperfetto Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73895 0.2 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21524151 t lperfetto P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry. SIGNOR-173425 0.873 SIGNOR-PCP p53 in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242609 0.7 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 t lperfetto Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 SIGNOR-153908 0.435 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. SIGNOR-126753 0.839 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74839 0.785 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 t Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis SIGNOR-33922 0.742 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75645 0.785 SIGNOR-PCP p53 in cancer BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75641 0.785 SIGNOR-PCP p53 in cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites SIGNOR-153475 0.785 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566157 t gcesareni The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry. SIGNOR-29248 0.873 SIGNOR-PCP p53 in cancer ATR protein Q13535 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 t gcesareni Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. SIGNOR-115134 0.73 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 8242752 t lperfetto The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. SIGNOR-37145 0.873 SIGNOR-PCP p53 in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t Cytosolic p53 amattioni P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization. SIGNOR-140242 0.742 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188408 0.747 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-75633 0.785 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.785 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-121895 0.742 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. SIGNOR-74835 0.785 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.785 SIGNOR-PCP p53 in cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.747 SIGNOR-PCP p53 in cancer MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 t gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. SIGNOR-115348 0.839 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74823 0.785 SIGNOR-PCP p53 in cancer DNA_damage extracellular stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 f lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. SIGNOR-242612 0.7 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 t gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. SIGNOR-158636 0.839 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 14963330 t lperfetto Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-178690 0.742 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.785 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153479 0.785 SIGNOR-PCP p53 in cancer CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245462 0.885 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75629 0.785 SIGNOR-PCP p53 in cancer BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. SIGNOR-167152 0.839 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9122197 f gcesareni P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis SIGNOR-47541 0.742 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 t gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 SIGNOR-77144 0.785 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 t lperfetto Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage. SIGNOR-126757 0.839 SIGNOR-PCP p53 in cancer ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-158324 0.747 SIGNOR-PCP p53 in cancer CHEK2 protein O96017 UNIPROT TP53 factor protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153483 0.785 SIGNOR-PCP p53 in cancer TP53 factor protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 f gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. SIGNOR-34962 0.968 SIGNOR-PD Parkinson UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 9521656 t lperfetto These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains SIGNOR-249693 0.857 SIGNOR-PD Parkinson LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 21658387 t lperfetto A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. SIGNOR-174044 0.388 SIGNOR-PD Parkinson PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 17906618 t gcesareni Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress. SIGNOR-158052 0.633 SIGNOR-PD Parkinson HTRA2 protein O43464 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 11583623 t gcesareni Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo. SIGNOR-110834 0.701 SIGNOR-PD Parkinson MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-252599 0.928 SIGNOR-PD Parkinson CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-PD Parkinson SNCA extracellular protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 12666095 f lperfetto A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. SIGNOR-249700 0.7 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 t lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis SIGNOR-56484 0.92 SIGNOR-PD Parkinson AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 t lperfetto Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. SIGNOR-119488 0.642 SIGNOR-PD Parkinson MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-217869 0.928 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding -1 12620238 t lperfetto This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity. SIGNOR-98988 0.92 SIGNOR-PD Parkinson DNAJC14 protein Q6Y2X3 UNIPROT ROS extracellular stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 15525720 f lperfetto Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson€™s disease. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to in- creased levels of oxidative stress. SIGNOR-249698 0.7 SIGNOR-PD Parkinson Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 f lperfetto The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur. SIGNOR-249703 0.7 SIGNOR-PD Parkinson CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. SIGNOR-53585 0.876 SIGNOR-PD Parkinson AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t lperfetto Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-252581 0.769 SIGNOR-PD Parkinson AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation SIGNOR-252585 0.769 SIGNOR-PD Parkinson PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT up-regulates activity phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 t lperfetto Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells SIGNOR-249691 0.583 SIGNOR-PD Parkinson CASP3 protein P42574 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-89244 0.7 SIGNOR-PD Parkinson AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-252472 0.769 SIGNOR-PD Parkinson ROS extracellular stimulus SIGNOR-ST2 SIGNOR SNCA extracellular protein P37840 UNIPROT up-regulates quantity 9606 16000336 f lperfetto The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. SIGNOR-249699 0.7 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 t amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). SIGNOR-71954 0.938 SIGNOR-PD Parkinson LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling SIGNOR-252598 0.388 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 t amattioni Xiap is an endogenous inhibitor of caspase-3 SIGNOR-110837 0.938 SIGNOR-PD Parkinson LRRK2 protein Q5S007 UNIPROT SNCA extracellular protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19576176 t lperfetto Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. SIGNOR-249690 0.651 SIGNOR-PD Parkinson UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 9606 BTO:0000938 26161729 t lperfetto Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-249692 0.2 SIGNOR-PD Parkinson CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-PD Parkinson AKT1 protein P31749 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 SIGNOR-252500 0.332 SIGNOR-PD Parkinson PINK1 protein Q9BXM7 UNIPROT CYCS protein P99999 UNIPROT down-regulates quantity 9606 BTO:0000938 20012177 t lperfetto There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy SIGNOR-249704 0.397 SIGNOR-PD Parkinson PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 BTO:0000007 22724072 t PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 SIGNOR-270345 0.2 SIGNOR-PD Parkinson MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-170604 0.928 SIGNOR-PD Parkinson PRKN protein O60260 UNIPROT SNCA extracellular protein P37840 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000938 12666095 t lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). SIGNOR-249705 0.2 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11447297 t lperfetto Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect. SIGNOR-109243 0.938 SIGNOR-PD Parkinson SNCA extracellular protein P37840 UNIPROT ER stress extracellular stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 f lperfetto Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. SIGNOR-249702 0.7 SIGNOR-PD Parkinson PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 t llicata We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1. SIGNOR-197976 0.2 SIGNOR-PD Parkinson XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 11242052 t lperfetto A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis SIGNOR-105702 0.92 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) STAT3 protein P40763 UNIPROT VEGFA extracellular protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12545153 t luana Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.  SIGNOR-259456 0.779 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216992 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 25309941 f Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). SIGNOR-255489 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) STAT1/STAT3 complex SIGNOR-C118 SIGNOR JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR form complex binding 10090 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235658 0.689 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. SIGNOR-216988 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256180 0.528 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.628 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.82 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFA extracellular protein P01135 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.895 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 0.703 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 0.691 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) EGFR receptor protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 14967450 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. SIGNOR-121965 0.876 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 t lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. SIGNOR-196116 0.968 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. SIGNOR-255693 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-244292 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256287 0.586 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.691 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) RB1 protein P06400 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245483 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-252698 0.728 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) EGFR receptor protein P00533 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR up-regulates activity phosphorylation 9606 15284024 t Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-252088 0.61 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 f miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. SIGNOR-127610 0.441 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TP53 factor protein P04637 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts SIGNOR-255669 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) RB1 protein P06400 UNIPROT E2F1 factor protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.917 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256181 0.628 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.785 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 0.701 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.82 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TERT protein O14746 UNIPROT Immortality phenotypesList phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers SIGNOR-252292 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250760 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) ErbB receptor family receptor proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256168 0.772 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) VEGFA extracellular protein P15692 UNIPROT Angiogenesis phenotypesList phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252275 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade. SIGNOR-250647 0.642 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CDK4 protein P11802 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR form complex binding 9606 7736585 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-32301 0.964 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-244296 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.701 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) E2F1 factor protein Q01094 UNIPROT G1/S_transition phenotypesList phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-245477 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 t luana The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-259810 0.803 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 t gcesareni We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2. SIGNOR-46758 0.874 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 0.703 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) MDM2 protein Q00987 UNIPROT TP53 factor protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 t lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity SIGNOR-199371 0.968 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) EGFR receptor protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-252672 0.772 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250759 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 0.701 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 t lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. SIGNOR-216957 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244357 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 0.703 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) TP53 factor protein P04637 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-255678 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) EGFR receptor protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 22693070 t lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. SIGNOR-235692 0.876 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 t lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) SIGNOR-244300 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256286 0.586 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244361 0.2 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 t llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. SIGNOR-250762 0.857 SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-PGC PPARgamma in cancer Fatty acid extracellular stimulus SIGNOR-ST19 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates 9606 29369787 t miannu Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system SIGNOR-256189 0.7 SIGNOR-PGC PPARgamma in cancer RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates activity binding 9606 11237216 t miannu Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-259057 0.2 SIGNOR-PGC PPARgamma in cancer all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256190 0.8 SIGNOR-PGC PPARgamma in cancer RXR proteinfamily SIGNOR-PF44 SIGNOR RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity binding 9606 1310351 t miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-256199 0.706 SIGNOR-PGC PPARgamma in cancer RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity binding 9606 1310351 t miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-256198 0.706 SIGNOR-PGC PPARgamma in cancer CTNNB1 protein P35222 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 0.56 SIGNOR-PGC PPARgamma in cancer CTNNB1 protein P35222 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates activity binding 10090 BTO:0003346 16847334 t Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain SIGNOR-256072 0.56 SIGNOR-PGC PPARgamma in cancer all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256197 0.8 SIGNOR-PGC PPARgamma in cancer PPARG factor protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20303941 f gcesareni The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. SIGNOR-164516 0.56 SIGNOR-PGC PPARgamma in cancer CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-PGC PPARgamma in cancer CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-PGC PPARgamma in cancer PPARG factor protein P37231 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 0.7 SIGNOR-PGC PPARgamma in cancer PPARG factor protein P37231 UNIPROT Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-256229 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253006 0.671 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252825 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252839 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255842 0.482 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252448 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252744 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-PI3K-AKT PI3K/AKT Signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252454 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. SIGNOR-247992 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253005 0.671 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129200 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252836 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252938 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-252676 0.486 SIGNOR-PI3K-AKT PI3K/AKT Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 17306385 t miannu The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos. SIGNOR-256167 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129196 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252451 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252838 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252743 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 t lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-236690 0.754 SIGNOR-PI3K-AKT PI3K/AKT Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. SIGNOR-157533 0.772 SIGNOR-PI3K-AKT PI3K/AKT Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-PI3K-AKT PI3K/AKT Signaling CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252746 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252827 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256166 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-217008 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling EIF4E protein P06730 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253007 0.671 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-251983 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-PI3K-AKT PI3K/AKT Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-PI3K-AKT PI3K/AKT Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252831 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 21157483 t lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism SIGNOR-251982 0.634 SIGNOR-PI3K-AKT PI3K/AKT Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-PI3K-AKT PI3K/AKT Signaling GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotypesList phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. SIGNOR-235751 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.72 SIGNOR-PI3K-AKT PI3K/AKT Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252829 0.909 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252742 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252745 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-252796 0.478 SIGNOR-PI3K-AKT PI3K/AKT Signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-PI3K-AKT PI3K/AKT Signaling RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252794 0.478 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252741 0.749 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129192 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-PI3K-AKT PI3K/AKT Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-PI3K-AKT PI3K/AKT Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-217137 0.754 SIGNOR-PI3K-AKT PI3K/AKT Signaling mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217086 0.754 SIGNOR-PI3K-AKT PI3K/AKT Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-PI3K-AKT PI3K/AKT Signaling HRAS protein P01112 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 8052307 t lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-252689 0.839 SIGNOR-PI3K-AKT PI3K/AKT Signaling PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248627 0.887 SIGNOR-PI3K-AKT PI3K/AKT Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-PI3K-AKT PI3K/AKT Signaling GF extracellular proteinfamily SIGNOR-PF39 SIGNOR RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR up-regulates activity binding 9606 17306385 t miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. SIGNOR-256163 0.2 SIGNOR-PI3K-AKT PI3K/AKT Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129188 0.2 SIGNOR-PPP Pentose phosphate pathway 2-deoxy-alpha-D-ribose 1-phosphate smallmolecule CHEBI:11563 ChEBI 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity precursor of 9606 17804405 t miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. SIGNOR-267093 0.8 SIGNOR-PPP Pentose phosphate pathway G6PD protein P11413 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267052 0.8 SIGNOR-PPP Pentose phosphate pathway PGD protein P52209 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-267061 0.8 SIGNOR-PPP Pentose phosphate pathway NFE2L2 factor protein Q16236 UNIPROT TKT protein P29401 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267356 0.272 SIGNOR-PPP Pentose phosphate pathway sedoheptulose smallmolecule CHEBI:16802 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 22682222 t miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose SIGNOR-268137 0.8 SIGNOR-PPP Pentose phosphate pathway RBKS protein Q9H477 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 25749547 t miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. SIGNOR-267073 0.8 SIGNOR-PPP Pentose phosphate pathway DERA protein Q9Y315 UNIPROT acetaldehyde smallmolecule CHEBI:15343 ChEBI up-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267099 0.8 SIGNOR-PPP Pentose phosphate pathway ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267055 0.8 SIGNOR-PPP Pentose phosphate pathway D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267062 0.8 SIGNOR-PPP Pentose phosphate pathway alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267074 0.8 SIGNOR-PPP Pentose phosphate pathway 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267096 0.8 SIGNOR-PPP Pentose phosphate pathway MYC factor protein P01106 UNIPROT NFE2L2 factor protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267363 0.539 SIGNOR-PPP Pentose phosphate pathway NFE2L2 factor protein Q16236 UNIPROT PGD protein P52209 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267355 0.287 SIGNOR-PPP Pentose phosphate pathway D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267063 0.8 SIGNOR-PPP Pentose phosphate pathway G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267051 0.8 SIGNOR-PPP Pentose phosphate pathway D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268132 0.8 SIGNOR-PPP Pentose phosphate pathway ROS extracellular stimulus SIGNOR-ST2 SIGNOR NFE2L2 factor protein Q16236 UNIPROT up-regulates 9606 BTO:0000018 22789539 f miannu Nrf2 is a master transcriptional activator of cytoprotective genes. It activates transcription in response to electrophiles and reactive oxygen species (ROS) (Itoh et al., 1997, Uruno and Motohashi, 2011). Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2. SIGNOR-267353 0.7 SIGNOR-PPP Pentose phosphate pathway D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268140 0.8 SIGNOR-PPP Pentose phosphate pathway sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268135 0.8 SIGNOR-PPP Pentose phosphate pathway NFE2L2 factor protein Q16236 UNIPROT TALDO1 protein P37837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267357 0.38 SIGNOR-PPP Pentose phosphate pathway TALDO1 protein P37837 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267091 0.8 SIGNOR-PPP Pentose phosphate pathway 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity precursor of 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267056 0.8 SIGNOR-PPP Pentose phosphate pathway TP53 factor protein P04637 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity binding 9606 BTO:0001938;BTO:0001109 21336310 t miannu The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. SIGNOR-267468 0.572 SIGNOR-PPP Pentose phosphate pathway PGLS protein O95336 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity chemical modification 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267058 0.8 SIGNOR-PPP Pentose phosphate pathway alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity precursor of 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267049 0.8 SIGNOR-PPP Pentose phosphate pathway D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates activity 9606 31108873 f De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis. SIGNOR-267387 0.7 SIGNOR-PPP Pentose phosphate pathway 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-267059 0.8 SIGNOR-PPP Pentose phosphate pathway RPE protein Q96AT9 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267068 0.8 SIGNOR-PPP Pentose phosphate pathway PGD protein P52209 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267053 0.8 SIGNOR-PPP Pentose phosphate pathway TKT protein P29401 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267088 0.8 SIGNOR-PPP Pentose phosphate pathway MYC factor protein P01106 UNIPROT PRPS2 protein P11908 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267376 0.283 SIGNOR-PPP Pentose phosphate pathway D-ribofuranose smallmolecule CHEBI:47013 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 25749547 t miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. SIGNOR-267071 0.8 SIGNOR-PPP Pentose phosphate pathway ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267054 0.8 SIGNOR-PPP Pentose phosphate pathway PGM2 protein Q96G03 UNIPROT 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity chemical modification 9606 17804405 t miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. SIGNOR-267095 0.8 SIGNOR-PPP Pentose phosphate pathway D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267077 0.8 SIGNOR-PPP Pentose phosphate pathway PRPS1 protein P60891 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267079 0.8 SIGNOR-PPP Pentose phosphate pathway D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268141 0.8 SIGNOR-PPP Pentose phosphate pathway D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267064 0.8 SIGNOR-PPP Pentose phosphate pathway PRPS2 protein P11908 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267082 0.8 SIGNOR-PPP Pentose phosphate pathway PGM2 protein Q96G03 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267076 0.8 SIGNOR-PPP Pentose phosphate pathway TKT protein P29401 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267087 0.8 SIGNOR-PPP Pentose phosphate pathway SHPK protein Q9UHJ6 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity phosphorylation 9606 22682222 t miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose SIGNOR-267084 0.8 SIGNOR-PPP Pentose phosphate pathway RPEL1 protein Q2QD12 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267069 0.8 SIGNOR-PPP Pentose phosphate pathway RPIA protein P49247 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267070 0.8 SIGNOR-PPP Pentose phosphate pathway DERA protein Q9Y315 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 25229427 t miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. SIGNOR-267098 0.8 SIGNOR-PPP Pentose phosphate pathway D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267080 0.8 SIGNOR-PPP Pentose phosphate pathway NFE2L2 factor protein Q16236 UNIPROT G6PD protein P11413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267354 0.338 SIGNOR-PPP Pentose phosphate pathway TALDO1 protein P37837 UNIPROT D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267092 0.8 SIGNOR-PU Ubiquitin activation Ub:RING_E3 complex SIGNOR-C519 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271383 0.7 SIGNOR-PU Ubiquitin activation UBA6 protein A0AVT1 UNIPROT Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270835 0.2 SIGNOR-PU Ubiquitin activation UCHL3 protein P15374 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270832 0.864 SIGNOR-PU Ubiquitin activation Ub:RBR_E3 complex SIGNOR-C520 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271384 0.7 SIGNOR-PU Ubiquitin activation Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270836 0.725 SIGNOR-PU Ubiquitin activation USP7 protein Q93009 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270837 0.772 SIGNOR-PU Ubiquitin activation Ub:E2 complex SIGNOR-C497 SIGNOR HECT E3 ligase proteinfamily SIGNOR-PF104 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270943 0.2 SIGNOR-PU Ubiquitin activation USP5 protein P45974 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270830 0.838 SIGNOR-PU Ubiquitin activation Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270834 0.753 SIGNOR-PU Ubiquitin activation Ub:E2 complex SIGNOR-C497 SIGNOR RBR E3 ligase proteinfamily SIGNOR-PF107 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270945 0.2 SIGNOR-PU Ubiquitin activation RBR E3 ligase proteinfamily SIGNOR-PF107 SIGNOR Ub:RBR_E3 complex SIGNOR-C520 SIGNOR form complex binding 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271378 0.2 SIGNOR-PU Ubiquitin activation Ub:E2 complex SIGNOR-C497 SIGNOR RING E3 ligase proteinfamily SIGNOR-PF106 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270944 0.2 SIGNOR-PU Ubiquitin activation RING E3 ligase proteinfamily SIGNOR-PF106 SIGNOR Ub:RING_E3 complex SIGNOR-C519 SIGNOR form complex binding 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271377 0.2 SIGNOR-PU Ubiquitin activation Ub:HECT_E3 complex SIGNOR-C518 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271382 0.7 SIGNOR-PU Ubiquitin activation OTULIN protein Q96BN8 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270829 0.698 SIGNOR-PU Ubiquitin activation Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270841 0.2 SIGNOR-PU Ubiquitin activation Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270840 0.2 SIGNOR-PU Ubiquitin activation USP9X protein Q93008 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270831 0.627 SIGNOR-PU Ubiquitin activation E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR Ub:E2 complex SIGNOR-C497 SIGNOR form complex ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270842 0.2 SIGNOR-PU Ubiquitin activation HECT E3 ligase proteinfamily SIGNOR-PF104 SIGNOR Ub:HECT_E3 complex SIGNOR-C518 SIGNOR form complex binding 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271376 0.2 SIGNOR-PU Ubiquitin activation UBA1 protein P22314 UNIPROT Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270833 0.2 SIGNOR-RAM Retinoic Acid Metabolism retinol extracellular smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265112 0.8 SIGNOR-RAM Retinoic Acid Metabolism RDH10 protein Q8IZV5 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265120 0.8 SIGNOR-RAM Retinoic Acid Metabolism retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265121 0.8 SIGNOR-RAM Retinoic Acid Metabolism RDH5 protein Q92781 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265114 0.8 SIGNOR-RAM Retinoic Acid Metabolism RBP1 protein P09455 UNIPROT retinol extracellular smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 31963453 t lperfetto Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking SIGNOR-265108 0.8 SIGNOR-RAM Retinoic Acid Metabolism STRA6 receptor protein Q9BX79 UNIPROT retinol extracellular smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9913 17255476 t lperfetto We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex SIGNOR-265107 0.8 SIGNOR-RAM Retinoic Acid Metabolism RBP2 protein P50120 UNIPROT all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity relocalization 9606 31963453 t lperfetto Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs) SIGNOR-265130 0.8 SIGNOR-RAM Retinoic Acid Metabolism ALDH1A2 protein O94788 UNIPROT all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265126 0.8 SIGNOR-RAM Retinoic Acid Metabolism ALDH1A1 protein P00352 UNIPROT all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265123 0.8 SIGNOR-RAM Retinoic Acid Metabolism retinol extracellular smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265118 0.8 SIGNOR-RAM Retinoic Acid Metabolism CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI down-regulates quantity chemical modification 9606 31963453 t lperfetto Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development SIGNOR-265139 0.8 SIGNOR-RAM Retinoic Acid Metabolism retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265127 0.8 SIGNOR-RAM Retinoic Acid Metabolism retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265124 0.8 SIGNOR-RAM Retinoic Acid Metabolism RBP4 extracellular protein P02753 UNIPROT retinol extracellular smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9606 31963453 t lperfetto In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4) SIGNOR-265106 0.8 SIGNOR-RAM Retinoic Acid Metabolism ALDH1A3 protein P47895 UNIPROT all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265129 0.8 SIGNOR-RAM Retinoic Acid Metabolism retinol extracellular smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265115 0.8 SIGNOR-RAM Retinoic Acid Metabolism DHRS9 protein Q9BPW9 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265117 0.8 SIGNOR-RAS Retinoic acid Signaling HES1 factor protein Q14469 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265140 0.357 SIGNOR-RAS Retinoic acid Signaling CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-RAS Retinoic acid Signaling CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t Through Armadillo repeat domain gcesareni Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential. SIGNOR-236858 0.766 SIGNOR-RAS Retinoic acid Signaling NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 t Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-254381 0.949 SIGNOR-RAS Retinoic acid Signaling ASCL1 factor protein P50553 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 24243019 f lperfetto Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1|Accordingly, Ascl1-mutant mice show severe defects in neurogenesis SIGNOR-265174 0.7 SIGNOR-RAS Retinoic acid Signaling RARG factor protein P13631 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16659 0.665 SIGNOR-RAS Retinoic acid Signaling HES1 factor protein Q14469 UNIPROT ASCL1 factor protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000931 11054669 f miannu Our data show that functional sympathetic neuronal differentiation of neuroblastoma cells is associated with transient activation of HES-1 and down-regulation of HASH-1 expression. SIGNOR-254824 0.458 SIGNOR-RAS Retinoic acid Signaling RARB factor protein P10826 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16519 0.66 SIGNOR-RAS Retinoic acid Signaling RBPJ/NOTCH factor complex SIGNOR-C97 SIGNOR HES1 factor protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 t lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-209590 0.673 SIGNOR-RAS Retinoic acid Signaling RXRA factor protein P19793 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12771132 t gcesareni Rxr agonists still inactivated endogenous beta-catenin via rxr alpha. SIGNOR-101293 0.429 SIGNOR-RAS Retinoic acid Signaling HES1 factor protein Q14469 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265142 0.327 SIGNOR-RAS Retinoic acid Signaling all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI RARA factor protein P10276 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258138 0.8 SIGNOR-RAS Retinoic acid Signaling all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI RARB factor protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258137 0.8 SIGNOR-RAS Retinoic acid Signaling NEUROG2 protein Q9H2A3 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis SIGNOR-265173 0.7 SIGNOR-RAS Retinoic acid Signaling RARA factor protein P10276 UNIPROT RXRA factor protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-16433 0.705 SIGNOR-RAS Retinoic acid Signaling all-trans-retinoic acid factor smallmolecule CHEBI:15367 ChEBI RARG factor protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258030 0.8 SIGNOR-RAS Retinoic acid Signaling NEUROG1 protein Q92886 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis SIGNOR-265172 0.7 SIGNOR-ReS Rett syndrome FKBP5 protein Q13451 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 30685540 f Luana Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. SIGNOR-265798 0.7 SIGNOR-ReS Rett syndrome SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-146897 0.809 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT GAMT protein Q14353 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264678 0.286 SIGNOR-ReS Rett syndrome MECP2/SIN3A/HDAC complex factor complex SIGNOR-C360 SIGNOR BDNF extracellular protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004102 14593184 t Luana Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter. SIGNOR-265071 0.385 SIGNOR-ReS Rett syndrome SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-ReS Rett syndrome CREB1 factor protein P16220 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 f Luana These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation. SIGNOR-265773 0.7 SIGNOR-ReS Rett syndrome HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-ReS Rett syndrome BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT IGFBP3 extracellular protein P17936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 17278996 f miannu We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. SIGNOR-254580 0.255 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264675 0.297 SIGNOR-ReS Rett syndrome MEF2C factor protein Q06413 UNIPROT MECP2 factor protein P51608 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 f Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. SIGNOR-254025 0.358 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT DLL1 extracellular protein O00548 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264674 0.2 SIGNOR-ReS Rett syndrome GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000601 25420914 f Luana Our current study highlights the phosphorylation, but not the overall expression level, of MeCP2 as a significant regulatory mechanism in regulating adult neurogenesis in the hippocampus.  SIGNOR-264967 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000478 26214522 f Luana  We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. SIGNOR-264552 0.2 SIGNOR-ReS Rett syndrome DLX5 factor protein P56178 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates -1 19195802 f Luana DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. SIGNOR-265797 0.7 SIGNOR-ReS Rett syndrome GAMT protein Q14353 UNIPROT Neurite_outgrowth phenotypesList phenotype SIGNOR-PH134 SIGNOR up-regulates -1 26319512 f Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system SIGNOR-265795 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT MEF2C factor protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264680 0.358 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1 SIGNOR-264682 0.553 SIGNOR-ReS Rett syndrome miR-27b mirna URS000075B0A5_9606 RNAcentral PPARG factor protein P37231 UNIPROT down-regulates quantity post transcriptional regulation 10116 26239616 t Luana Overexpression of miR-132 significantly reduced the expression levels of MeCP2, at both the mRNA and protein level, whereas downregulation of miR-132 increased the mRNA and protein expression levels of MeCP2 SIGNOR-264608 0.4 SIGNOR-ReS Rett syndrome PTPN1 protein P18031 UNIPROT NTRK2 receptor protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling SIGNOR-264553 0.388 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254579 0.383 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 f Luana Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2 SIGNOR-264966 0.7 SIGNOR-ReS Rett syndrome NTRK2 receptor protein Q16620 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9507002 t gcesareni Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors SIGNOR-55864 0.741 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT DNMT1 factor protein P26358 UNIPROT up-regulates activity binding 9606 BTO:0000007 12473678 t Luana Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity. SIGNOR-264541 0.551 SIGNOR-ReS Rett syndrome miR-495 mirna URS000075C517_9606 RNAcentral Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 26344767 t Luana To further determine whether MeCP2 regulates the expression of miR-199a, we also re-expressed MeCP2 in MeCP2-KO neurons. As expected, this restored the level of mature-miR-199a expression to that in WT neurons SIGNOR-264545 0.4 SIGNOR-ReS Rett syndrome SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-147865 0.809 SIGNOR-ReS Rett syndrome CDKL5 protein O76039 UNIPROT MECP2 factor protein P51608 UNIPROT unknown phosphorylation -1 16935860 t Luana Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity SIGNOR-264702 0.628 SIGNOR-ReS Rett syndrome HIPK2 protein Q9H2X6 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. SIGNOR-264551 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT MECP2/SIN3A/HDAC complex factor complex SIGNOR-C360 SIGNOR form complex binding 10116 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-265070 0.688 SIGNOR-ReS Rett syndrome HIPK2 protein Q9H2X6 UNIPROT MECP2 factor protein P51608 UNIPROT up-regulates activity phosphorylation SeR80 AVPEASAsPKQRRSI 9606 BTO:0000007 19820693 t Luana Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo. SIGNOR-264549 0.495 SIGNOR-ReS Rett syndrome PTPN1 protein P18031 UNIPROT NTRK2 receptor protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr706 RDVYSTDyYRVGGHT 9606 BTO:0000793 26214522 t Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling SIGNOR-264554 0.388 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT RELN extracellular protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254578 0.394 SIGNOR-ReS Rett syndrome NOTCH1 protein P46531 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR down-regulates 10090 9601631 f Luana Signalling through activated Notch is known both to control multiple cell fate determinations (in both invertebrates and vertebrates) and to inhibit developmental processes, such as neurogenesis SIGNOR-265769 0.7 SIGNOR-ReS Rett syndrome GRIA2 receptor protein P42262 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones. SIGNOR-265796 0.7 SIGNOR-ReS Rett syndrome GPRIN1 protein Q7Z2K8 UNIPROT Neurite_outgrowth phenotypesList phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 22956546 f Luana  GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells. SIGNOR-265799 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT GRIA2 receptor protein P42262 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 22262897 t Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. SIGNOR-264684 0.333 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 t Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. SIGNOR-264542 0.315 SIGNOR-ReS Rett syndrome DLL1 extracellular protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209732 0.606 SIGNOR-ReS Rett syndrome DNMT1 factor protein P26358 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254574 0.36 SIGNOR-ReS Rett syndrome RELN extracellular protein P78509 UNIPROT Synaptic_plasticity phenotypesList phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 17584923 f Luana Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity SIGNOR-265772 0.7 SIGNOR-ReS Rett syndrome miR-27a mirna URS0000233054_9606 RNAcentral PPARG factor protein P37231 UNIPROT down-regulates quantity post transcriptional regulation 10090 26344767 f Luana We also found that miR-199a expression and blockade (see below for details) potentiated and attenuated, respectively, the phosphorylation levels in neurons of S6 ribosomal protein, which signify the activation of mTOR signaling, indicating that miR-199a positively regulates mTOR signaling activity SIGNOR-265770 0.4 SIGNOR-ReS Rett syndrome IGFBP3 extracellular protein P17936 UNIPROT Neuron_maturation phenotypesList phenotype SIGNOR-PH169 SIGNOR down-regulates 10090 BTO:0000142 17278996 f Luana IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation. SIGNOR-265774 0.7 SIGNOR-ReS Rett syndrome ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 f Luana Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. SIGNOR-264978 0.7 SIGNOR-ReS Rett syndrome MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-ReS Rett syndrome MEF2C factor protein Q06413 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates -1 23001426 f Luana  In brain, MEF2C is essential for early neurogenesis, neuronal migration, and differentiation.  SIGNOR-265800 0.7 SIGNOR-ReS Rett syndrome MTOR protein P42345 UNIPROT Neurogenesis phenotypesList phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 f Luana The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation. SIGNOR-265771 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT DLX5 factor protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19195802 f Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain SIGNOR-254034 0.393 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 26214522 t Luana In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT. SIGNOR-264546 0.2 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT Neuron_maturation phenotypesList phenotype SIGNOR-PH169 SIGNOR up-regulates 10090 BTO:0000601 17532643 f Luana Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis. SIGNOR-264968 0.7 SIGNOR-ReS Rett syndrome GAMT protein Q14353 UNIPROT Neuron_maturation phenotypesList phenotype SIGNOR-PH169 SIGNOR up-regulates -1 26319512 f Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system SIGNOR-265794 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 f Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. SIGNOR-264550 0.7 SIGNOR-ReS Rett syndrome MECP2 factor protein P51608 UNIPROT GPRIN1 protein Q7Z2K8 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264679 0.306 SIGNOR-ReS Rett syndrome miR-29a mirna URS00004E9304_9606 RNAcentral TET2 protein Q6N021 UNIPROT down-regulates quantity by repression post transcriptional regulation 10116 17994015 t Luana Here, we show that MeCP2 levels are repressed by miR132, a brain-enriched microRNA (miRNA). We propose that the interaction of miR132 with its miRNA recognition element (MRE) in the MeCP2 3′ UTR prevents MeCP2 levels from becoming deleteriously high during neuronal maturation. SIGNOR-264703 0.4 SIGNOR-ReS Rett syndrome BDNF extracellular protein P23560 UNIPROT NTRK2 receptor protein Q16620 UNIPROT up-regulates binding 9606 7679912 t gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb SIGNOR-31597 0.812 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 0.2 SIGNOR-RMS Rhabdomyosarcoma MYOG factor protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells SIGNOR-251575 0.342 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246244 0.2 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247197 0.559 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166718 0.561 SIGNOR-RMS Rhabdomyosarcoma PAX3 factor protein P23760 UNIPROT TBX2 factor protein Q13207 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3 SIGNOR-249596 0.357 SIGNOR-RMS Rhabdomyosarcoma TBX2 factor protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 f TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells SIGNOR-251563 0.7 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates activity binding 9606 BTO:0000222 16982699 t lperfetto More importantly, the consequences of phosphorylation of either Thr145 or Ser146 are distinct. When p21 is phosphorylated on Thr145, it localizes to the nucleus and results in the disruption of the association between proliferating cell nuclear antigen and p21. Furthermore, phosphorylation of Thr145 promotes stabilization of p21 SIGNOR-244187 0.2 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-RMS Rhabdomyosarcoma GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 t lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. SIGNOR-83343 0.423 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 t lperfetto IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro SIGNOR-236548 0.35 SIGNOR-RMS Rhabdomyosarcoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.737 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 t lperfetto We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation. SIGNOR-246373 0.66 SIGNOR-RMS Rhabdomyosarcoma MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250289 0.658 SIGNOR-RMS Rhabdomyosarcoma PDGFRA receptor protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. SIGNOR-254377 0.331 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25194572 f miannu Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus. SIGNOR-255416 0.541 SIGNOR-RMS Rhabdomyosarcoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.743 SIGNOR-RMS Rhabdomyosarcoma TBX2 factor protein Q13207 UNIPROT MYOG factor protein P15173 UNIPROT down-regulates activity binding 9606 24470334 t We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. SIGNOR-251561 0.253 SIGNOR-RMS Rhabdomyosarcoma FGFR4 receptor protein P22455 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251142 0.414 SIGNOR-RMS Rhabdomyosarcoma PAX7 factor protein P23759 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-219371 0.7 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. SIGNOR-135984 0.432 SIGNOR-RMS Rhabdomyosarcoma PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.812 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. SIGNOR-244618 0.2 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252350 0.2 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 t lperfetto We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation. SIGNOR-244513 0.2 SIGNOR-RMS Rhabdomyosarcoma MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250552 0.658 SIGNOR-RMS Rhabdomyosarcoma PDGFRA receptor protein P16234 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 15489898 t gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. SIGNOR-247984 0.464 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-244180 0.2 SIGNOR-RMS Rhabdomyosarcoma MET receptor protein P08581 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 22128289 t irozzo For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. SIGNOR-256261 0.68 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 f lperfetto The upregulation of p21 occurred at the levels of mrna and protein, SIGNOR-235831 0.417 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 f Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation SIGNOR-254353 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246264 0.559 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 9566874 t lperfetto Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. SIGNOR-235445 0.782 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45126 0.559 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-RMS Rhabdomyosarcoma MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-RMS Rhabdomyosarcoma PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 t lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-244429 0.812 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246276 0.559 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 f In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. SIGNOR-256256 0.7 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246252 0.2 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-RMS Rhabdomyosarcoma KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 f miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). SIGNOR-260082 0.641 SIGNOR-RMS Rhabdomyosarcoma PDGFA extracellular protein P04085 UNIPROT PDGFRA receptor protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 t gcesareni Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity. SIGNOR-114268 0.763 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival SIGNOR-254948 0.7 SIGNOR-RMS Rhabdomyosarcoma MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-244222 0.2 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair SIGNOR-245048 0.7 SIGNOR-RMS Rhabdomyosarcoma TBX2 factor protein Q13207 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates activity binding 9606 24470334 t We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. SIGNOR-251560 0.319 SIGNOR-RMS Rhabdomyosarcoma TBX2 factor protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249593 0.357 SIGNOR-RMS Rhabdomyosarcoma MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259110 0.7 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259919 0.2 SIGNOR-RMS Rhabdomyosarcoma MYC factor protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102743 0.759 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246248 0.2 SIGNOR-RMS Rhabdomyosarcoma MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250288 0.658 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 10373569 t gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. SIGNOR-238529 0.417 SIGNOR-RMS Rhabdomyosarcoma IGF1 extracellular protein P05019 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 0.955 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 t Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. SIGNOR-255640 0.432 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 18316399 t gcesareni We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity. SIGNOR-161113 0.423 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 t lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. SIGNOR-217514 0.822 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129200 0.2 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 21408055 f andrea cerquone perpetuini Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling. SIGNOR-255413 0.745 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 0.2 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.822 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129196 0.2 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-RMS Rhabdomyosarcoma PDGFB extracellular protein P01127 UNIPROT PDGFRA receptor protein P16234 UNIPROT up-regulates activity binding 9606 11331882 t miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107397 0.706 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236302 0.692 SIGNOR-RMS Rhabdomyosarcoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOD1 factor protein P15172 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216969 0.448 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 t Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. lperfetto The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2 SIGNOR-235917 0.867 SIGNOR-RMS Rhabdomyosarcoma PIK3CA protein P42336 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 t gcesareni Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects. SIGNOR-47152 0.644 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-RMS Rhabdomyosarcoma MYC factor protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102740 0.773 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt. SIGNOR-244184 0.2 SIGNOR-RMS Rhabdomyosarcoma PAX7 factor protein P23759 UNIPROT MYOD1 factor protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 f Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 0.624 SIGNOR-RMS Rhabdomyosarcoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 t lperfetto In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. SIGNOR-247341 0.782 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. SIGNOR-244396 0.73 SIGNOR-RMS Rhabdomyosarcoma KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. SIGNOR-175204 0.907 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166710 0.35 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45130 0.559 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 0.2 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-246377 0.66 SIGNOR-RMS Rhabdomyosarcoma MYOG factor protein P15173 UNIPROT PAX7 factor protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 f Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions SIGNOR-255638 0.513 SIGNOR-RMS Rhabdomyosarcoma FOXO1 factor protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0000007 25510553 t miannu FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. SIGNOR-263496 0.58 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247193 0.559 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 f miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254952 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166722 0.561 SIGNOR-RMS Rhabdomyosarcoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-RMS Rhabdomyosarcoma HGF extracellular protein P14210 UNIPROT MET receptor protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene. SIGNOR-38429 0.927 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37458 0.7 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 t lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26586 0.2 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129188 0.2 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 0.2 SIGNOR-RMS Rhabdomyosarcoma RB1 protein P06400 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-262533 0.7 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129192 0.2 SIGNOR-RMS Rhabdomyosarcoma PAX3 factor protein P23760 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181621 0.502 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-RMS Rhabdomyosarcoma CTNNB1 protein P35222 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 18316399 t Simone Vumbaca Together, these results suggest that B-Cat increases MyoD binding to E box elements SIGNOR-255653 0.423 SIGNOR-RMS Rhabdomyosarcoma CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 0.2 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 0.2 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246268 0.559 SIGNOR-RMS Rhabdomyosarcoma MET receptor protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250290 0.658 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-244225 0.2 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252352 0.2 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246272 0.559 SIGNOR-RMS Rhabdomyosarcoma TBX2 factor protein Q13207 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells SIGNOR-251562 0.7 SIGNOR-RMS Rhabdomyosarcoma IGF2 extracellular protein P01344 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity binding 9606 22810696 t lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. SIGNOR-251495 0.817 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC factor protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. SIGNOR-252079 0.2 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT HGF extracellular protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11278729 t lperfetto Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells SIGNOR-251742 0.608 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 9606 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236314 0.692 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236318 0.692 SIGNOR-RMS Rhabdomyosarcoma CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 f gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. SIGNOR-69925 0.703 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 t miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246260 0.2 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 0.2 SIGNOR-RMS Rhabdomyosarcoma STAT3 protein P40763 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-246368 0.66 SIGNOR-RMS Rhabdomyosarcoma SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166714 0.35 SIGNOR-RMS Rhabdomyosarcoma MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 0.7 SIGNOR-RMS Rhabdomyosarcoma IGF1R receptor protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 t lperfetto We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376 SIGNOR-236544 0.35 SIGNOR-RMS Rhabdomyosarcoma GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-RMS Rhabdomyosarcoma PAX7 factor protein P23759 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 f lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181624 0.624 SIGNOR-RMS Rhabdomyosarcoma ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr317 PPTPGNTyQIPRTFP 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236306 0.692 SIGNOR-RMS Rhabdomyosarcoma AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-257606 0.7 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 t Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter SIGNOR-255639 0.432 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 8940173 t lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor SIGNOR-45122 0.559 SIGNOR-RMS Rhabdomyosarcoma BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-RMS Rhabdomyosarcoma IGF1 extracellular protein P05019 UNIPROT IGF1R receptor protein P08069 UNIPROT up-regulates activity binding 9606 21798082 t lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 0.955 SIGNOR-RMS Rhabdomyosarcoma PAX3 factor protein P23760 UNIPROT FGFR4 receptor protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS. SIGNOR-251572 0.378 SIGNOR-RMS Rhabdomyosarcoma PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-RMS Rhabdomyosarcoma FGF1 extracellular protein P05230 UNIPROT FGFR4 receptor protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18454 0.819 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT MYOG factor protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 f gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. SIGNOR-235009 0.432 SIGNOR-RMS Rhabdomyosarcoma CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOG factor protein P15173 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216972 0.349 SIGNOR-RMS Rhabdomyosarcoma MYOD1 factor protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates transcriptional regulation 9606 25211658 t P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells SIGNOR-251574 0.417 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 11481331 t lperfetto Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1. SIGNOR-109533 0.561 SIGNOR-RMS Rhabdomyosarcoma SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr259 ASVDSSLyNLPRSYS 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236310 0.692 SIGNOR-RS RTKs in cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-RS RTKs in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-RS RTKs in cancer PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-RS RTKs in cancer GF extracellular proteinfamily SIGNOR-PF39 SIGNOR RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR up-regulates activity binding 9606 17306385 t miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. SIGNOR-256163 0.2 SIGNOR-RS RTKs in cancer HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-RS RTKs in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. SIGNOR-249628 0.8 SIGNOR-RS RTKs in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-RS RTKs in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254374 0.7 SIGNOR-RS RTKs in cancer SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-RS RTKs in cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-RS RTKs in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-RS RTKs in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-RS RTKs in cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-RS RTKs in cancer HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-RS RTKs in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-RS RTKs in cancer RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 17306385 t miannu The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos. SIGNOR-256167 0.2 SIGNOR-RS RTKs in cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-RS RTKs in cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-RS RTKs in cancer RTKs receptor proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256166 0.2 SIGNOR-RS RTKs in cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-RS RTKs in cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 f areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. SIGNOR-255120 0.7 SIGNOR-RS RTKs in cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 t lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. SIGNOR-236490 0.8 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 t miannu Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73 SIGNOR-250133 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. SIGNOR-236455 0.489 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 t gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). SIGNOR-98399 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t The effect has been demonstrated using O43521-2 gcesareni Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes SIGNOR-98396 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 t gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). SIGNOR-178686 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250126 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 9922370 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-64175 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 t simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex SIGNOR-256022 0.528 SIGNOR-SAPK-JNK SAPK/JNK Signaling SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 t gcesareni We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli. SIGNOR-145393 0.29 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.748 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-44356 0.489 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein. SIGNOR-124012 0.54 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0001271 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-160326 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8. gcesareni Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax SIGNOR-124020 0.38 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP4K2 protein Q12851 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 9712898 t gcesareni The mekk1 associated with the gck carboxyl terminus is catalytically active. SIGNOR-59682 0.541 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody. SIGNOR-43999 0.326 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-235407 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ELK1 factor protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 t lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-236432 0.489 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). SIGNOR-251419 0.736 SIGNOR-SAPK-JNK SAPK/JNK Signaling JUN factor protein P05412 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 10871633 t irozzo These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity. SIGNOR-256284 0.74 SIGNOR-SAPK-JNK SAPK/JNK Signaling TNFRSF1B receptor protein P20333 UNIPROT TRAF1 receptor protein Q13077 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33133 0.709 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250127 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-59689 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser15 GLGGGAAsPPAASPF 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250123 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.748 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-SAPK-JNK SAPK/JNK Signaling CRK protein P46108 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated Crk mainly on threonine and weakly on serine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63988 0.673 SIGNOR-SAPK-JNK SAPK/JNK Signaling BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 BTO:0000007 11997495 t lperfetto We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome. SIGNOR-87280 0.823 SIGNOR-SAPK-JNK SAPK/JNK Signaling SH3RF1 protein Q7Z6J0 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 9482736 t gcesareni Posh activates jnk1 in cos-1 cells. SIGNOR-55759 0.385 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250125 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 22492984 t lperfetto Bim, and puma bind with high affinity to all pro-survival proteins SIGNOR-196935 0.823 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 f gcesareni These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells. SIGNOR-67321 0.531 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250124 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-178655 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling TNFRSF1B receptor protein P20333 UNIPROT TRAF1 receptor protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33843 0.709 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-179456 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-250132 0.751 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.692 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 SIGNOR-236376 0.712 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250128 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. SIGNOR-162638 0.575 SIGNOR-SAPK-JNK SAPK/JNK Signaling RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 t gcesareni These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108260 0.427 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 t gcesareni Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. SIGNOR-179476 0.7 SIGNOR-SAPK-JNK SAPK/JNK Signaling RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108257 0.427 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 SIGNOR-59679 0.427 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation SIGNOR-67552 0.7 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32421 0.771 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates binding 9606 9712898 t gcesareni Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2. SIGNOR-59685 0.508 SIGNOR-SAPK-JNK SAPK/JNK Signaling GRB2 protein P62993 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t gcesareni The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2. SIGNOR-63994 0.467 SIGNOR-SAPK-JNK SAPK/JNK Signaling SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. SIGNOR-96952 0.319 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8IP1 protein Q9UQF2 UNIPROT MAP4K2 protein Q12851 UNIPROT down-regulates binding 9606 BTO:0000007 10702297 t gcesareni DLK mutants were used to demonstrate that a DLK leucine zipper-leucine zipper interaction is necessary for DLK dimerization and to show that DLK dimerization mediated by the leucine zipper domain is prerequisite for DLK activity and subsequent activation of stress-activated protein kinase (SAPK). SIGNOR-75385 0.2 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 t JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660). gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. SIGNOR-70851 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 10090 12242151 t lperfetto We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. SIGNOR-92939 0.823 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32425 0.771 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7824938 t gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. SIGNOR-33914 0.771 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily. SIGNOR-42384 0.2 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 15141161 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-124727 0.88 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-42984 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly, SIGNOR-43996 0.427 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT TRAF1 receptor protein Q13077 UNIPROT up-regulates binding 9606 8069916 t amattioni Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-35881 0.612 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7824938 t gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. SIGNOR-33918 0.771 SIGNOR-SAPK-JNK SAPK/JNK Signaling BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 17289999 t lperfetto Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak SIGNOR-152986 0.823 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 t We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-256252 0.889 SIGNOR-SAPK-JNK SAPK/JNK Signaling TNFRSF1B receptor protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 8069916 t lperfetto Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. SIGNOR-34645 0.696 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT NFATC2 factor protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter. SIGNOR-118217 0.74 SIGNOR-SAPK-JNK SAPK/JNK Signaling TRAF1 receptor protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 t gcesareni Traf1 and traf2 can form homo- and heterotypic dimers. SIGNOR-34768 0.612 SIGNOR-SAPK-JNK SAPK/JNK Signaling MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-160323 0.751 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. SIGNOR-135384 0.787 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0005029 25271362 f Luana Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein. SIGNOR-260200 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 t Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease SIGNOR-73898 0.687 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 t Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. SIGNOR-50585 0.787 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS S extracellular protein P59594 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 f Luana We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner SIGNOR-260219 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 f Luana In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. SIGNOR-260204 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 f Luana SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway SIGNOR-260205 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS N protein P59595 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. SIGNOR-260199 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 3b protein P59633 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 16965829 f Luana Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells SIGNOR-260194 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 6 protein P59634 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 f Luana A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis SIGNOR-260203 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 7a protein P59635 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260209 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 7b protein Q7TFA1 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. SIGNOR-260210 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.789 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.617 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT down-regulates activity binding 9606 9539746 t lperfetto These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1. SIGNOR-56399 0.836 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. SIGNOR-251473 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS FAS receptor protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.906 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0001950 18632968 f Luana Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation SIGNOR-260193 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-260443 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.59 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002552 33188728 f miannu We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells SIGNOR-262506 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-53582 0.617 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP8 protein Q14790 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni Downstream of caspase-8 activation, apoptosis induction takes place SIGNOR-90612 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000093 22464442 t lperfetto Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer. SIGNOR-209675 0.85 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-131442 0.817 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 14965271 t lperfetto Fas (CD95) is activated by its natural ligand FasL SIGNOR-216292 0.9 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.838 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS FASLG extracellular protein P48023 UNIPROT FAS receptor protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 t lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) SIGNOR-49688 0.9 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.617 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.617 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 7a protein P59635 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 17428862 t Luana In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family. SIGNOR-261075 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS E protein P59637 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity 9606 BTO:0000661 16048439 f Luana SARS-CoV E protein induces apoptosis by ‘sequestering’ Bcl-xL to the membranes of ER and Golgi, where the SARS-CoV E protein is located. As a consequence, the existing balance between pro-survival protein Bcl-xL and pro-apoptotic proteins, including Bax and BH3-domain-only proteins, is tipped by SARS CoV E protein, so that sequestered Bcl-xL could not fulfil its normal function in inhibition of apoptosis. | This result implied that SARS-CoV E protein might induce T-cell apoptosis via a pathway antagonistic to the mitochondrion-dependent mechanism of Bcl-xL. SIGNOR-260586 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp403 LPAADMDdFSRQLQN 9534 BTO:0001444 18155731 t Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 SIGNOR-260212 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp400 VTLLPAAdMDDFSRQ 9534 BTO:0001444 18155731 t Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 SIGNOR-260211 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. SIGNOR-53585 0.876 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BCL2L1 protein Q07817 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 9670005 t amattioni The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal. SIGNOR-59141 0.727 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 8a protein Q7TFA0 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 f Luana Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis SIGNOR-260206 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 3a protein P59632 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 18632968 f Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. SIGNOR-260213 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS M protein P59596 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 25271362 f Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  SIGNOR-260202 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-59857 0.716 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS ER stress extracellular stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196944 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS 3a protein P59632 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 18632968 f Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. SIGNOR-260214 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 t lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. SIGNOR-149574 0.787 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS ER stress extracellular stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196941 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS AKT proteinfamily SIGNOR-PF24 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates -1 14663477 f Luana Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt. SIGNOR-260215 0.7 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 BTO:0000007 11997495 t lperfetto We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome. SIGNOR-87280 0.823 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 t lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . SIGNOR-135381 0.953 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. SIGNOR-36898 0.615 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS M protein P59596 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity 9606 25271362 f Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  SIGNOR-260201 0.2 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 t lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. SIGNOR-126727 0.515 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 t gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w SIGNOR-151787 0.718 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.787 SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236110 0.736 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260723 0.71 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION AP1 factor complex SIGNOR-C154 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 t Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity SIGNOR-260764 0.602 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 t Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-260722 0.57 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 t gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 0.44 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 10480932 t Luana P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-260720 0.728 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 9430721 t Luana The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms SIGNOR-260721 0.728 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 f Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer SIGNOR-260766 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity 9606 21561061 f Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260761 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION EGF extracellular protein P01133 UNIPROT EGFR receptor protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION selumetinib extracellular chemical CHEBI:90227 ChEBI ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 t Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  SIGNOR-262313 0.8 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ATF2 factor protein P15336 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 f Luana ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. SIGNOR-261324 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION N protein P59595 UNIPROT ATF2 factor protein P15336 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 t Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well SIGNOR-260727 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21561061 f Luana 3b Augments c-Fos Levels by Activating the ERK Pathway. | An increase of∼2.0-fold inphospho ERK (Thr-202/Tyr-204) levels in 3b-expressing Huh7cells as compared to GFP-transfected control cells (Figure 4a)was observed. This increase in phospho ERK levels was also SIGNOR-260763 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION E protein P59637 UNIPROT SDCBP extracellular protein O00560 UNIPROT up-regulates activity relocalization 9534 25122212 t Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. SIGNOR-260752 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION IL6 extracellular protein P05231 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260256 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo. SIGNOR-261133 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION DDIT3 factor protein P35638 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.812 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 t lperfetto Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-83729 0.736 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION CREB1 factor protein P16220 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-261288 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 t Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  SIGNOR-262312 0.8 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. SIGNOR-141641 0.84 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION N protein P59595 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 t Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well SIGNOR-260729 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.82 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION SDCBP extracellular protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0001444 25122212 f Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. SIGNOR-260753 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION N protein P59595 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 14623261 t Luana Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway. SIGNOR-260725 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 3b protein P59633 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 21561061 f Luana SARS-CoV Accessory Protein 3b Induces AP-1 TranscriptionalActivity SIGNOR-260757 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION p38 proteinfamily SIGNOR-PF16 SIGNOR DDIT3 factor protein P35638 UNIPROT up-regulates activity phosphorylation -1 8650547 t Luana Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase SIGNOR-260724 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 t Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244952 0.733 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0001950 18632968 f Luana Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation SIGNOR-260193 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 7a protein P59635 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000007 16378980 f Luana While there is a low level of activated p38 normally found in 293T cells, expression of 7a-protein stimulated larger amounts of activated p38 during the 24-h time course.  SIGNOR-260754 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION E protein P59637 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 10090 BTO:0000763 25122212 f Luana Interestingly, an increase in p38 MAPK activation was observed during infection with viruses containing E protein PBM, similarly to what was observed in the lungs of SARS-CoV-infected mice. These results indicated that the E protein PBM is involved in p38 MAPK activation in response to SARS-CoV infection. SIGNOR-260751 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ATF2 factor protein P15336 UNIPROT IL6 extracellular protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254512 0.306 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION CCL2 extracellular protein P13500 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 f Luana In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. SIGNOR-261317 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002552 33188728 f miannu We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells SIGNOR-262506 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t Luana Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. SIGNOR-260755 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION BCL2 protein P10415 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis SIGNOR-249611 0.7 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION EGFR receptor protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 t lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). SIGNOR-235721 0.921 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION N protein P59595 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0000298 15294014 f Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. SIGNOR-261132 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9534 15294014 f Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. SIGNOR-261131 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 21561061 f Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260760 0.2 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0001950 21561061 t Luana Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP SIGNOR-260759 0.736 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.838 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation Ser67 RQLRKVRsVELDQLP 9606 12228228 t gcesareni Activation of ras may lead to two distinct ras-dependent pathways involving either a raf1/mek/mapk module or a mekk/sek/sapk module; jnk/sapk binds to the d domain near the nh2 terminus of mekk1 from approximately residues 6270 (9, 10). Pak1 can phosphorylate mekk1 on serine 67 within its jnk/sapk-binding d domain. Phosphorylation of mekk1 on serine 67 alters the state of the d domain, thereby decreasing its affinity for jnk/sapk. Under these conditions jnk/sapk is not recruited into the mekk1 signaling module. SIGNOR-92793 0.376 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 SIGNOR-59679 0.427 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Camostat extracellular chemical CID:2536 ChEBI TMPRSS2 receptor protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 32142651 t miannu Indeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells (Figure 4 A). Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260284 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Spike protein-ACE2 receptor complex SIGNOR-C240 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 f miannu Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260289 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY SACM1L protein Q9NTJ5 UNIPROT phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI down-regulates quantity chemical modification 9534 22253445 t lperfetto To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P. SIGNOR-260733 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAS1 receptor protein P04201 UNIPROT AGTR1 receptor protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 t miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex SIGNOR-260626 0.282 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. SIGNOR-260741 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY aloxistatin extracellular chemical CHEBI:101381 ChEBI CTSL protein P07711 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260282 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY AP-2/clathrin vescicle receptor complex SIGNOR-C249 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260704 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260744 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY aloxistatin extracellular chemical CHEBI:101381 ChEBI CTSB protein P07858 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 t miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260281 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY AGTR1 receptor protein P30556 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260629 0.503 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 f miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. SIGNOR-260743 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CoV2 spike protein-NRP1 receptor complex SIGNOR-C267 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 10090 BTO:0000108 33082293 t Luana NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice. SIGNOR-262316 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT MAS1 receptor protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CTSL protein P07711 UNIPROT S extracellular protein P59594 UNIPROT up-regulates activity cleavage -1 16081529 t miannu A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection. SIGNOR-260218 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P0DTC2 UNIPROT CoV2 spike protein-NRP1 receptor complex SIGNOR-C267 SIGNOR form complex binding 9606 BTO:0000007 other t https://doi.org/10.1101/2020.06.07.137802 miannu Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c) SIGNOR-261671 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. SIGNOR-260745 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Spike protein-ACE2 receptor complex SIGNOR-C240 SIGNOR AP-2/clathrin vescicle receptor complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260711 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 16988814 t miannu In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of ANG II from ANG I is enhanced by ACE, and ANG II induces acute lung failure through stimulation of the AT1 receptor, while ACE2 and ANG II type 2 receptor negatively regulate this pathway and protect from acute lung failure. On the other hand, SARS-CoV infection is mediated through binding of the SARS-Spike protein to ACE2 or L-SIGN and down-regulates the protective molecule ACE2, and thus leads to severe lung injury and acute lung failure SIGNOR-260291 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY NRP1 extracellular protein O14786 UNIPROT CoV2 spike protein-NRP1 receptor complex SIGNOR-C267 SIGNOR form complex binding 9606 BTO:0000007 other t https://doi.org/10.1101/2020.06.07.137802 miannu Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c) SIGNOR-261672 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY TMPRSS2 receptor protein O15393 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32142651 t miannu Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells SIGNOR-260736 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY FURIN receptor protein P09958 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0002750 32362314 t Luana Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. SIGNOR-262305 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY TMPRSS4 receptor protein Q9NRS4 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32404436 t Luana TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion. SIGNOR-262306 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.682 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka. SIGNOR-126659 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR AP-2/clathrin vescicle receptor complex SIGNOR-C249 SIGNOR up-regulates 17522231 f lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins SIGNOR-260756 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAS1 receptor protein P04201 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 9606 26460884 t miannu We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases SIGNOR-260627 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P0DTC2 UNIPROT CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 t miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. SIGNOR-260739 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CTSL protein P07711 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 t miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260737 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFITMs receptor proteinfamily SIGNOR-PF49 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 25599080 f miannu The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons SIGNOR-260220 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY N protein P59595 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260337 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY 3b protein P59633 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260338 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY PI4KB protein Q9UBF8 UNIPROT phosphatidylinositol 4-phosphate receptor smallmolecule CHEBI:37530 ChEBI up-regulates quantity chemical modification 9534 22253445 t lperfetto Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry. SIGNOR-260732 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY CTSB protein P07858 UNIPROT S extracellular protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 t miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. SIGNOR-260738 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY 6 protein P59634 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260339 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAS1 receptor protein P04201 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51199 0.682 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P0DTC2 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 32125455 t miannu SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. SIGNOR-260742 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY ACE2 receptor protein Q9BYF1 UNIPROT CoV2 Spike protein-ACE2 receptor complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 t miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. SIGNOR-260740 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9534 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260283 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY 8a protein Q7TFA0 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. SIGNOR-260239 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY ACE2 receptor protein Q9BYF1 UNIPROT Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY 8b protein Q80H93 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. SIGNOR-260240 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY AGTR1 receptor protein P30556 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260234 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAPK8 protein P45983 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant SIGNOR-183489 0.555 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 14670965 t miannu The coronavirus spike (S) protein mediates infection of receptor-expressing host cells and is a critical target for antiviral neutralizing antibodies. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for the coronavirus (severe acute respiratory syndrome (SARS)-CoV) that causes SARS. Here we demonstrate that a 193-amino acid fragment of the S protein (residues 318-510) bound ACE2 more efficiently than did the full S1 domain (residues 12-672). Smaller S protein fragments, expressing residues 327-510 or 318-490, did not detectably bind ACE2. SIGNOR-260216 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY chloroquine extracellular chemical CHEBI:3638 ChEBI ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 t miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells SIGNOR-260223 0.8 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY ACE2 receptor protein Q9BYF1 UNIPROT Spike protein-ACE2 receptor complex SIGNOR-C240 SIGNOR form complex binding 9534 BTO:0001444 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260288 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY S extracellular protein P59594 UNIPROT Spike protein-ACE2 receptor complex SIGNOR-C240 SIGNOR form complex binding 9534 BTO:0001444 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260287 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY TMPRSS2 receptor protein O15393 UNIPROT S extracellular protein P59594 UNIPROT up-regulates activity cleavage 9606 32142651 t miannu Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. SIGNOR-260217 0.2 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260628 0.264 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY IFITMs receptor proteinfamily SIGNOR-PF49 SIGNOR S extracellular protein P59594 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0004126 29263263 f miannu All three IFITMs significantly inhibited the infection by lentiviral particles pseudotyped with IAV hemagglutinin 1 (H1) and neuraminidase 1 (N1) (IAVpp), Spike protein (S) of HCoV-229E (229Epp), HCoV-NL63 (NL63pp), SARS-CoV (SARSpp), and MERS-CoV (MERSpp) in both HEK293 (Fig. 1B) and Huh7.5 (Fig. 1C) cells. SIGNOR-260230 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Macrophage_activation phenotype SIGNOR-PH126 SIGNOR IL18 extracellular protein Q14116 UNIPROT up-regulates quantity 9606 BTO:0000801 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. SIGNOR-260964 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM TNF extracellular protein P01375 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 f andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 0.666 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL6ST receptor protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 0.66 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNG extracellular protein P01579 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261024 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260348 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM AP1 factor complex SIGNOR-C154 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 t Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity SIGNOR-260764 0.602 SIGNOR-SCCS SARS-CoV CYTOKINE STORM STAT3 protein P40763 UNIPROT IL10 extracellular protein P22301 UNIPROT up-regulates transcriptional regulation 9606 28713870 f svumbaca These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression SIGNOR-256234 0.784 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL18 extracellular protein Q14116 UNIPROT IFNG extracellular protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. SIGNOR-260858 0.486 SIGNOR-SCCS SARS-CoV CYTOKINE STORM CCL7 extracellular protein P80098 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260850 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261035 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNAR receptor complex SIGNOR-C243 SIGNOR CCL7 extracellular protein P80098 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260852 0.281 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL10 extracellular protein P22301 UNIPROT IL10RA receptor protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 t lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 0.911 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL12A extracellular protein P29459 UNIPROT IFNG extracellular protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 SIGNOR-260859 0.378 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR TNF extracellular protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 0.666 SIGNOR-SCCS SARS-CoV CYTOKINE STORM TNF extracellular protein P01375 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261034 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL6R receptor protein P08887 UNIPROT IL6ST receptor protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 t gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. SIGNOR-105504 0.736 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL7 extracellular protein P80098 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260963 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNB1 extracellular protein P01574 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260335 0.761 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL10 extracellular protein P22301 UNIPROT IL1RN extracellular protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. SIGNOR-254793 0.601 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNA1 extracellular protein P01562 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260334 0.631 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR CXCL8 extracellular protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260974 0.633 SIGNOR-SCCS SARS-CoV CYTOKINE STORM STAT1 factor protein P42224 UNIPROT IRF7 factor protein Q92985 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 16628196 f miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. SIGNOR-255231 0.503 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL6 extracellular protein P05231 UNIPROT IL6R receptor protein P08887 UNIPROT up-regulates activity binding 9606 18923185 t miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. SIGNOR-255324 0.916 SIGNOR-SCCS SARS-CoV CYTOKINE STORM JAK1 protein P23458 UNIPROT STAT1 factor protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 0.784 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT JUN factor protein P05412 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu SARS-CoV nsp1 inhibits c-Jun expression and phosphorylation. SIGNOR-262505 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM chloroquine extracellular chemical CHEBI:3638 ChEBI IL6 extracellular protein P05231 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260854 0.8 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR STAT1 factor protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 0.666 SIGNOR-SCCS SARS-CoV CYTOKINE STORM 6 protein P59634 UNIPROT STAT1 factor protein P42224 UNIPROT down-regulates activity relocalization 9606 17108024 f miannu ORF 6 protein inhibits the translocation of STAT1.SARS-CoV ORF 6 protein, but not ORF 3b or N protein, was able to inhibit the translocation of STAT1-GFP to the nucleus. A higher magnification of the image of ORF 6 protein in cells transfected with STAT1-GFP and treated with IFN-β shows that ORF 6 protein does not colocalize with STAT1, indicating that ORF 6 does not directly interact with STAT1 SIGNOR-260341 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNAR receptor complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 SIGNOR-SCCS SARS-CoV CYTOKINE STORM JUN factor protein P05412 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR form complex binding -1 2467839 t irozzo The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation. SIGNOR-256361 0.951 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) SIGNOR-254509 0.566 SIGNOR-SCCS SARS-CoV CYTOKINE STORM N protein P59595 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 14623261 t Luana Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway. SIGNOR-260725 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM S extracellular protein P59594 UNIPROT TLR2 receptor protein O60603 UNIPROT up-regulates activity binding 9606 BTO:0001025 19185596 t miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. SIGNOR-260972 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM EIF2AK2 protein P19525 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260159 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM TNF extracellular protein P01375 UNIPROT IL6 extracellular protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) SIGNOR-260856 0.528 SIGNOR-SCCS SARS-CoV CYTOKINE STORM STAT1 factor protein P42224 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 t 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 SIGNOR-240606 0.67 SIGNOR-SCCS SARS-CoV CYTOKINE STORM TLR2 receptor protein O60603 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0001025 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260973 0.546 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL1R1 receptor protein P14778 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9625767 f lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab) SIGNOR-249512 0.505 SIGNOR-SCCS SARS-CoV CYTOKINE STORM chloroquine extracellular chemical CHEBI:3638 ChEBI TNF extracellular protein P01375 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260853 0.8 SIGNOR-SCCS SARS-CoV CYTOKINE STORM 3a protein P59632 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR down-regulates quantity 9606 20020050 f miannu The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity. SIGNOR-260350 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM 3b protein P59633 UNIPROT AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity 9606 21561061 f Luana SARS-CoV Accessory Protein 3b Induces AP-1 TranscriptionalActivity SIGNOR-260757 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT STAT1 factor protein P42224 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. SIGNOR-262502 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). SIGNOR-187775 0.794 SIGNOR-SCCS SARS-CoV CYTOKINE STORM CCL2 extracellular protein P13500 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260849 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Macrophage_activation phenotype SIGNOR-PH126 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261021 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNAR receptor complex SIGNOR-C243 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260851 0.325 SIGNOR-SCCS SARS-CoV CYTOKINE STORM T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR IFNG extracellular protein P01579 UNIPROT up-regulates quantity 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260967 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR IL6 extracellular protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255357 0.622 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IRF7 factor protein Q92985 UNIPROT IFNA1 extracellular protein P01562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16612387 f gcesareni Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. SIGNOR-146119 0.563 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261022 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL12A extracellular protein P29459 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260966 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNAR receptor complex SIGNOR-C243 SIGNOR Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260848 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Tocilizumab extracellular antibody DB06273 DRUGBANK IL6R receptor protein P08887 UNIPROT down-regulates activity binding 9606 32446778 t doi: 10.1016/j.cytogfr.2020.05.003 miannu Tocilizumab is a humanized anti-IL-6 receptor IgG1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases [14]. By blocking the IL-6-receptor interaction, Tocilizumab inhibits the IL-6-mediated signal transduction. Although clinical data on the use of Tocilizumab in COVID-19 patients derive from small series, some authors recommend its use in critically ill COVID-19 patients with significantly elevated IL-6 levels. SIGNOR-260857 0.4 SIGNOR-SCCS SARS-CoV CYTOKINE STORM AP1 factor complex SIGNOR-C154 SIGNOR CXCL8 extracellular protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f miannu The up-regulation of the CXCL8 gene expression, could be due to a direct effect of the virus at the cellular level. Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly increase their secretion of CXCL8 [88]. This observation would fit with the notion that the expression of CXCL8 is dependent on the tran-scription factor Activator protein 1 (AP-1), which was shown to bestrongly up-regulated by SARS-CoV SIGNOR-261029 0.566 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF7 factor protein Q92985 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262504 0.2 SIGNOR-SCCS SARS-CoV CYTOKINE STORM AP1 factor complex SIGNOR-C154 SIGNOR IL6 extracellular protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 f JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes SIGNOR-254513 0.629 SIGNOR-SCCS SARS-CoV CYTOKINE STORM CXCL8 extracellular protein P10145 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261030 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001412 8021507 t In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene. SIGNOR-255938 0.569 SIGNOR-SCCS SARS-CoV CYTOKINE STORM CCL2 extracellular protein P13500 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261027 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL1B extracellular protein P01584 UNIPROT IL1R1 receptor protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 0.903 SIGNOR-SCCS SARS-CoV CYTOKINE STORM ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260158 0.493 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260962 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL1RN extracellular protein P18510 UNIPROT IL1R1 receptor protein P14778 UNIPROT down-regulates activity binding 9606 2876877 t Gianni Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β SIGNOR-262302 0.893 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL6ST receptor protein P40189 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32234467 f miannu Interleukin-6 (IL-6) is an important member of the cytokine network and plays a central role in acute inflammation. IL-6 binds to its receptor IL-6R to form a complex, and then binds to the membrane protein gp130 to initiate intracellular signal transduction. IL-6 is the terminal helper factor of cytotoxic T lymphocyte (CTL), which can induce CTL activity and make immature thymocytes develop into CTL. In addition, IL-6 is a pro-inflammatory regulator of T cells. SIGNOR-261028 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM CXCL10 extracellular protein P02778 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261025 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261036 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL18 extracellular protein Q14116 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 f miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. SIGNOR-260965 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IFNG extracellular protein P01579 UNIPROT IFNGR2/INFGR1 receptor complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249487 0.757 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL10RA receptor protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68010 0.798 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL1B extracellular protein P01584 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261026 0.7 SIGNOR-SCCS SARS-CoV CYTOKINE STORM IL1B extracellular protein P01584 UNIPROT IL6 extracellular protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) SIGNOR-260855 0.536 SIGNOR-SCFI SARS-CoV FIBROSIS AGTR2 receptor protein P50052 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 32201502 f MIANNU AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth SIGNOR-260232 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR2 receptor protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT MAS1 receptor protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT up-regulates activity binding 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260226 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS MRGPRD protein Q8TDS7 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 10090 BTO:0000801 30918468 f Luana Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. SIGNOR-262310 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 t miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression SIGNOR-260437 0.593 SIGNOR-SCFI SARS-CoV FIBROSIS CGP-42112A chemical CHEBI:147302 ChEBI AGTR2 receptor protein P50052 UNIPROT down-regulates activity chemical inhibition -1 32278693 t Luana CGP42112A is an angiotensin AT2 (Angiotensin receptor 2) receptor agonist that may alleviate the virus-induced lung injury SIGNOR-262311 0.8 SIGNOR-SCFI SARS-CoV FIBROSIS TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260446 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS EP300 factor protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 t miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. SIGNOR-260431 0.726 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT Alamandine chemical CID:44192273 ChEBI up-regulates activity catalytic activity -1 24389733 t Luana Newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1–7). SIGNOR-262307 0.8 SIGNOR-SCFI SARS-CoV FIBROSIS SMAD7 protein O15105 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 30017632 t miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). SIGNOR-260438 0.781 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 24168260 f miannu We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis. SIGNOR-260447 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS REN extracellular protein P00797 UNIPROT Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260225 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS AGTR1 receptor protein P30556 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260233 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-SCFI SARS-CoV FIBROSIS MRGPRD protein Q8TDS7 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 23446738 f Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262309 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS TGFBR1 receptor protein P36897 UNIPROT SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 f miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. SIGNOR-260590 0.45 SIGNOR-SCFI SARS-CoV FIBROSIS chloroquine extracellular chemical CHEBI:3638 ChEBI ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 t miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells SIGNOR-260223 0.8 SIGNOR-SCFI SARS-CoV FIBROSIS S extracellular protein P0DTC2 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 32125455 t miannu SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. SIGNOR-260742 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS AGT extracellular protein P01019 UNIPROT REN extracellular protein P00797 UNIPROT up-regulates activity binding 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260224 0.927 SIGNOR-SCFI SARS-CoV FIBROSIS BCL2L11 protein O43521 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS MAS1 receptor protein P04201 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9534 18554741 t miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. SIGNOR-260283 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS N protein P59595 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein. SIGNOR-260340 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-SCFI SARS-CoV FIBROSIS SERPINE1 extracellular protein P05121 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 f miannu Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. SIGNOR-260588 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS N protein P59595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 18055455 t miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. SIGNOR-260434 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 14670965 t miannu The coronavirus spike (S) protein mediates infection of receptor-expressing host cells and is a critical target for antiviral neutralizing antibodies. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for the coronavirus (severe acute respiratory syndrome (SARS)-CoV) that causes SARS. Here we demonstrate that a 193-amino acid fragment of the S protein (residues 318-510) bound ACE2 more efficiently than did the full S1 domain (residues 12-672). Smaller S protein fragments, expressing residues 327-510 or 318-490, did not detectably bind ACE2. SIGNOR-260216 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260425 0.475 SIGNOR-SCFI SARS-CoV FIBROSIS TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-SCFI SARS-CoV FIBROSIS TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-SCFI SARS-CoV FIBROSIS N protein P59595 UNIPROT SERPINE1 extracellular protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18055455 f miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. SIGNOR-260589 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS N protein P59595 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR down-regulates quantity binding 9606 BTO:0000763 18055455 t miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. SIGNOR-260427 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-SCFI SARS-CoV FIBROSIS ACE receptor protein P12821 UNIPROT Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260236 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin-2 extracellular protein P01019-PRO_0000032458 UNIPROT AGTR1 receptor protein P30556 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260238 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS S extracellular protein P59594 UNIPROT ACE2 receptor protein Q9BYF1 UNIPROT down-regulates activity binding 9606 16988814 t miannu In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of ANG II from ANG I is enhanced by ACE, and ANG II induces acute lung failure through stimulation of the AT1 receptor, while ACE2 and ANG II type 2 receptor negatively regulate this pathway and protect from acute lung failure. On the other hand, SARS-CoV infection is mediated through binding of the SARS-Spike protein to ACE2 or L-SIGN and down-regulates the protective molecule ACE2, and thus leads to severe lung injury and acute lung failure SIGNOR-260291 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS ACE2 receptor protein Q9BYF1 UNIPROT Angiotensin 1-7 extracellular protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. SIGNOR-260227 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS Angiotensin-1 extracellular protein P01019-PRO_0000032457 UNIPROT ACE receptor protein P12821 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260231 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260445 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-SCFI SARS-CoV FIBROSIS Alamandine chemical CID:44192273 ChEBI MRGPRD protein Q8TDS7 UNIPROT up-regulates activity binding 10029 BTO:0000246 23446738 t Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262308 0.8 SIGNOR-SCFI SARS-CoV FIBROSIS SMAD3 protein P84022 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 SIGNOR-SCFI SARS-CoV FIBROSIS AGTR1 receptor protein P30556 UNIPROT Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. SIGNOR-260234 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Caspase 1 complex complex SIGNOR-C220 SIGNOR IL18 extracellular protein Q14116 UNIPROT up-regulates activity cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 t lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. SIGNOR-256377 0.785 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 3a protein P59632 UNIPROT IFNAR receptor complex SIGNOR-C243 SIGNOR down-regulates quantity 9606 20020050 f miannu The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity. SIGNOR-260350 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IFNAR receptor complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260147 0.727 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 9b protein P59636 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260242 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260329 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist SIGNOR-260248 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 6 protein P0DTC6 UNIPROT KPNA2 protein P52292 UNIPROT down-regulates activity binding 9606 32979938 t miannu The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F). SIGNOR-262513 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260149 0.716 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE N protein P59595 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein. SIGNOR-260340 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 f miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. SIGNOR-260346 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE N protein P59595 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260337 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 3b protein P59633 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260338 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 6 protein P59634 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260339 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 9b protein P59636 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260243 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 8a protein Q7TFA0 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. SIGNOR-260239 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE 8b protein Q80H93 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. SIGNOR-260240 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE N protein P59595 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0002181 16546436 t Luana SARS-CoV N protein activates COX-2 promoter and induces COX-2 protein expression SIGNOR-262314 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE S extracellular protein P59594 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity transcriptional regulation 9606 17267381 t Luana Spike protein of SARS‐CoV activated COX‐2 expression in a protein concentration‐dependent manner SIGNOR-262315 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR TNF extracellular protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255354 0.666 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3 SIGNOR-260246 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-172132 0.418 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256376 0.797 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256381 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-260151 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 t miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity SIGNOR-260160 0.92 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IFNAR receptor complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260146 0.8 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260148 0.721 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE EIF2AK2 protein P19525 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260159 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Non-structural protein 6 protein P0DTD1-PRO_0000449624 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262510 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR CCL2 extracellular protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255356 0.566 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE KPNA2 protein P52292 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity relocalization 9606 32979938 t miannu The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F). SIGNOR-262514 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260156 0.9 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 f miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. SIGNOR-260158 0.493 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.818 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 t Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. SIGNOR-256079 0.721 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE PTGS2 protein P35354 UNIPROT Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000007 32995789 f miannu Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice SIGNOR-262509 0.7 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.576 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0005029 25271362 f Luana Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein. SIGNOR-260200 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B extracellular protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -1 1919001 t lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  SIGNOR-256375 0.797 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262511 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 f miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 SIGNOR-260328 0.362 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR IFNAR receptor complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE IFNAR receptor complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262512 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. SIGNOR-216313 0.722 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260144 0.823 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260154 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 25636800 t miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. SIGNOR-260145 0.91 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260245 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. SIGNOR-216365 0.811 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA MAVS protein Q7Z434 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260152 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 f miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260190 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-260157 0.576 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260142 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA STING1 protein Q86WV6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. SIGNOR-260153 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262512 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260139 0.935 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262511 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA N protein P59595 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein. SIGNOR-260340 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA ORF4b protein K9N643 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity binding 9606 26631542 t miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm SIGNOR-260592 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Non-structural protein 6 protein P0DTD1-PRO_0000449624 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 32979938 t miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). SIGNOR-262510 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 t lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction SIGNOR-178053 0.622 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260191 0.33 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260141 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 6 protein P59634 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 f miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. SIGNOR-262517 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA IKBKE protein Q14164 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 t miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. SIGNOR-260155 0.622 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity binding 9606 22312431 t miannu Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING SIGNOR-260247 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260587 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA ORF4b protein K9N643 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 26631542 t miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm SIGNOR-260593 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA M protein P0DTC5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0000007 33110251 t miannu Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions. SIGNOR-262515 0.1 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA MAVS protein Q7Z434 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 t miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  SIGNOR-260143 0.794 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 9b protein P59636 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260241 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 t miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. SIGNOR-260192 0.271 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA IRF3 factor protein Q14653 UNIPROT Interferon-type-I extracellular proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 f miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-260330 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA N protein P59595 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260337 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 8b protein Q80H93 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. SIGNOR-260240 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 8a protein Q7TFA0 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. SIGNOR-260239 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260140 0.809 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 6 protein P59634 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260339 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 6 protein P0DTC6 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 f miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. SIGNOR-262516 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA 3b protein P59633 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260338 0.2 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-SCSG SARS-CoV STRESS GRANULES Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17715225 f miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. SIGNOR-262503 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES MAVS protein Q7Z434 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 t miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  SIGNOR-260143 0.794 SIGNOR-SCSG SARS-CoV STRESS GRANULES PPP2CA protein P67775 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 24726876 t miannu RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260944 0.318 SIGNOR-SCSG SARS-CoV STRESS GRANULES M protein P0DTC5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0000007 33110251 t miannu Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions. SIGNOR-262515 0.1 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260863 0.468 SIGNOR-SCSG SARS-CoV STRESS GRANULES 8b protein Q80H93 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. SIGNOR-260240 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260348 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 20573744 f miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. SIGNOR-260939 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP2 protein Q9UN86 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 10969074 t SARA IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm. SIGNOR-260985 0.348 SIGNOR-SCSG SARS-CoV STRESS GRANULES 9b protein P59636 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization 9606 25135833 f miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. SIGNOR-260241 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES 6 protein P59634 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 f miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. SIGNOR-262517 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260141 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES 8a protein Q7TFA0 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 t miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. SIGNOR-260239 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES N protein P59595 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260337 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260864 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES 6 protein P0DTC6 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 f miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. SIGNOR-262516 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES 3b protein P59633 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260338 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 t miannu We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization SIGNOR-260748 0.242 SIGNOR-SCSG SARS-CoV STRESS GRANULES NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-SCSG SARS-CoV STRESS GRANULES N protein P0DTC9 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity binding 9606 32353859 t miannu N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms SIGNOR-260749 SIGNOR-SCSG SARS-CoV STRESS GRANULES Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260867 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260862 0.468 SIGNOR-SCSG SARS-CoV STRESS GRANULES EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 t lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). SIGNOR-167176 0.938 SIGNOR-SCSG SARS-CoV STRESS GRANULES 6 protein P59634 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity 9606 17108024 f miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. SIGNOR-260339 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES EIF4E protein P06730 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex SIGNOR-236806 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 factor protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 t miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. SIGNOR-260750 0.315 SIGNOR-SCSG SARS-CoV STRESS GRANULES NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 f apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. SIGNOR-255693 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection SIGNOR-260747 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 11381086 f miannu Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis.  SIGNOR-260625 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 t gcesareni Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites. SIGNOR-98280 0.347 SIGNOR-SCSG SARS-CoV STRESS GRANULES LARP4B protein Q92615 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 20573744 f miannu Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs. SIGNOR-260942 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 24726876 t miannu RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260945 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260866 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 t miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. SIGNOR-260139 0.935 SIGNOR-SCSG SARS-CoV STRESS GRANULES Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260865 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES LARP4B protein Q92615 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260940 0.571 SIGNOR-SCSG SARS-CoV STRESS GRANULES EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR) SIGNOR-260168 0.715 SIGNOR-SCSG SARS-CoV STRESS GRANULES Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 BTO:0002552 33188728 t miannu Our structure of the SARS-CoV-2 Nsp1 protein bound to the 40S ribosomal subunit establishes a mechanistic basis of the cellular effects of Nsp1, revealing a multifaceted mechanism of inhibition of the host protein synthesis at the initiation stage by the virusThis shows that Nsp1 not only plugs the mRNA entry channel but also keeps the 40S subunit in a conformation that is incompatible with mRNA loading. SIGNOR-262518 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT up-regulates activity binding 9606 BTO:0005238 20573744 t miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. SIGNOR-260941 0.2 SIGNOR-SCSG SARS-CoV STRESS GRANULES 4E2RCat chemical CID:2287236 ChEBI EIF4E protein P06730 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 t miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. SIGNOR-260187 0.8 SIGNOR-SCSG SARS-CoV STRESS GRANULES 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto Ribosomes are translational machineries that catalyse protein synthesis. SIGNOR-262412 0.7 SIGNOR-SCSG SARS-CoV STRESS GRANULES PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT up-regulates activity binding 9606 30209168 t miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling SIGNOR-260968 0.799 SIGNOR-SCUP SARS-CoV ER STRESS Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 BTO:0002552 33188728 t miannu Our structure of the SARS-CoV-2 Nsp1 protein bound to the 40S ribosomal subunit establishes a mechanistic basis of the cellular effects of Nsp1, revealing a multifaceted mechanism of inhibition of the host protein synthesis at the initiation stage by the virusThis shows that Nsp1 not only plugs the mRNA entry channel but also keeps the 40S subunit in a conformation that is incompatible with mRNA loading. SIGNOR-262518 0.2 SIGNOR-SCUP SARS-CoV ER STRESS ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates activity 9606 31226023 f miannu The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK) SIGNOR-260177 0.325 SIGNOR-SCUP SARS-CoV ER STRESS Exosome_Complex complex SIGNOR-C255 SIGNOR XBP1 protein P17861-2 UNIPROT up-regulates quantity relocalization 9606 30319453 t miannu When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. Spliced form of XBP1 mRNA was incorporated into the exosomes of HEK293T cells, which overexpress IRE1α. We found that one of the ER stress signal-induced transcripts, sXBP1, was incorporated into the exosomes. Our results suggest that exosomes may play a vital role in the extracellular release of ER stress signals. SIGNOR-260946 0.2 SIGNOR-SCUP SARS-CoV ER STRESS Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 f miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260163 0.7 SIGNOR-SCUP SARS-CoV ER STRESS ATF4 factor protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260172 0.651 SIGNOR-SCUP SARS-CoV ER STRESS 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto Ribosomes are translational machineries that catalyse protein synthesis. SIGNOR-262412 0.7 SIGNOR-SCUP SARS-CoV ER STRESS EIF2S1 protein P05198 UNIPROT ATF4 factor protein P18848 UNIPROT down-regulates quantity transcriptional regulation 9606 27629041 t miannu ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery SIGNOR-260169 0.628 SIGNOR-SCUP SARS-CoV ER STRESS Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 f miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. SIGNOR-260167 0.7 SIGNOR-SCUP SARS-CoV ER STRESS EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR) SIGNOR-260168 0.715 SIGNOR-SCUP SARS-CoV ER STRESS ATF6 protein P18850 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260184 0.683 SIGNOR-SCUP SARS-CoV ER STRESS ATF6 protein P18850 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260180 0.647 SIGNOR-SCUP SARS-CoV ER STRESS ERN1 protein O75460 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 31226023 t miannu Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity. SIGNOR-260183 0.64 SIGNOR-SCUP SARS-CoV ER STRESS PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-260174 0.685 SIGNOR-SCUP SARS-CoV ER STRESS E protein P59637 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity 9534 BTO:0001444 22028656 f miannu SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. SIGNOR-260347 0.2 SIGNOR-SCUP SARS-CoV ER STRESS EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 11381086 f miannu Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis.  SIGNOR-260625 0.7 SIGNOR-SCUP SARS-CoV ER STRESS XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 f miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. SIGNOR-260186 0.7 SIGNOR-SCUP SARS-CoV ER STRESS EIF2AK3 protein Q9NZJ5 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates phosphorylation Tyr619 NKVDDCNyAIKRIRL 9606 17998206 t lperfetto We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity. SIGNOR-159156 0.2 SIGNOR-SCUP SARS-CoV ER STRESS HSPA5 protein P11021 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 31226023 t miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. SIGNOR-260164 0.715 SIGNOR-SCUP SARS-CoV ER STRESS S extracellular protein P59594 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 f miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. SIGNOR-260353 0.2 SIGNOR-SCUP SARS-CoV ER STRESS EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotypesList phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 31226023 f miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes. SIGNOR-260166 0.7 SIGNOR-SCUP SARS-CoV ER STRESS Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 f miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260175 0.7 SIGNOR-SCUP SARS-CoV ER STRESS PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity dephosphorylation 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-254119 0.425 SIGNOR-SCUP SARS-CoV ER STRESS S extracellular protein P59594 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 f miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. SIGNOR-260351 0.2 SIGNOR-SCUP SARS-CoV ER STRESS S extracellular protein P59594 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity 9606 16940539 f miannu SARS-CoV S protein specifically activated PERK but did not significantly affect IRE1/XBP1 or ATF6. SIGNOR-260439 0.2 SIGNOR-SCUP SARS-CoV ER STRESS DDIT3 factor protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260173 0.474 SIGNOR-SCUP SARS-CoV ER STRESS JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 f miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. SIGNOR-260178 0.7 SIGNOR-SCUP SARS-CoV ER STRESS Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 f miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. SIGNOR-260348 0.2 SIGNOR-SCUP SARS-CoV ER STRESS EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation. SIGNOR-260165 0.756 SIGNOR-SCUP SARS-CoV ER STRESS HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT down-regulates activity binding 9606 31226023 t miannu Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78 SIGNOR-260179 0.817 SIGNOR-SCUP SARS-CoV ER STRESS ATF4 factor protein P18848 UNIPROT DDIT3 factor protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260170 0.81 SIGNOR-SCUP SARS-CoV ER STRESS HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 9606 31226023 t miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260176 0.815 SIGNOR-SCUP SARS-CoV ER STRESS DDIT3 factor protein P35638 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 SIGNOR-SHB Sex Hormone Biosynthesis estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268661 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11A1 protein P05108 UNIPROT pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268632 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268639 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD17B11 protein Q8NBQ5 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268663 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD3B1 protein P14060 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268635 0.8 SIGNOR-SHB Sex Hormone Biosynthesis STAR protein P49675 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 17579211 t lperfetto StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone SIGNOR-265727 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B2 protein P19099 UNIPROT 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268684 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268647 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP21A2 protein P08686 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268645 0.8 SIGNOR-SHB Sex Hormone Biosynthesis progesterone smallmolecule CHEBI:17026 ChEBI 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268631 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD3B1 protein P14060 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. SIGNOR-268637 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD17B11 protein Q8NBQ5 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268666 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP19A1 protein P11511 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268670 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B2 protein P19099 UNIPROT aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268685 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD17B11 protein Q8NBQ5 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268664 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B2 protein P19099 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268676 0.8 SIGNOR-SHB Sex Hormone Biosynthesis androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268668 0.8 SIGNOR-SHB Sex Hormone Biosynthesis pregnenolone smallmolecule CHEBI:16581 ChEBI 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268648 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268643 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP17A1 protein P05093 UNIPROT dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268651 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD17B11 protein Q8NBQ5 UNIPROT androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268660 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD3B1 protein P14060 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268636 0.8 SIGNOR-SHB Sex Hormone Biosynthesis pregnenolone smallmolecule CHEBI:16581 ChEBI progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268630 0.8 SIGNOR-SHB Sex Hormone Biosynthesis cholesterol smallmolecule CHEBI:16113 ChEBI pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268629 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268673 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268650 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD3B2 protein P26439 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268634 0.8 SIGNOR-SHB Sex Hormone Biosynthesis androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. SIGNOR-268640 0.8 SIGNOR-SHB Sex Hormone Biosynthesis dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268641 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268669 0.8 SIGNOR-SHB Sex Hormone Biosynthesis HSD3B1 protein P14060 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268638 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268642 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268662 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268652 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B1 protein P15538 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268678 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B1 protein P15538 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268682 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268686 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268680 0.8 SIGNOR-SHB Sex Hormone Biosynthesis 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 9814482 t lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. SIGNOR-268675 0.8 SIGNOR-SHB Sex Hormone Biosynthesis progesterone smallmolecule CHEBI:17026 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268649 0.8 SIGNOR-SHB Sex Hormone Biosynthesis dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 30943210 t lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone SIGNOR-268659 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268653 0.8 SIGNOR-SHB Sex Hormone Biosynthesis androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268665 0.8 SIGNOR-SHB Sex Hormone Biosynthesis corticosterone smallmolecule CHEBI:16827 ChEBI 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268674 0.8 SIGNOR-SHB Sex Hormone Biosynthesis CYP17A1 protein P05093 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268654 0.8 SIGNOR-SHB Sex Hormone Biosynthesis testosterone smallmolecule CHEBI:17347 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268667 0.8 SIGNOR-TA TNF-alpha Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-TA TNF-alpha Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.799 SIGNOR-TA TNF-alpha Signaling CASP8 protein Q14790 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability. SIGNOR-71265 0.906 SIGNOR-TA TNF-alpha Signaling TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 t amattioni Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation SIGNOR-67552 0.7 SIGNOR-TA TNF-alpha Signaling RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 t gcesareni These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108260 0.427 SIGNOR-TA TNF-alpha Signaling TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 t gcesareni Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. SIGNOR-179476 0.7 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.864 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 t lperfetto Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161763 0.578 SIGNOR-TA TNF-alpha Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. SIGNOR-109716 0.923 SIGNOR-TA TNF-alpha Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-TA TNF-alpha Signaling MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51207 0.706 SIGNOR-TA TNF-alpha Signaling MAPK14 protein Q16539 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser347 FTGLKCPsLAGKPKV 9606 BTO:0000130 14970175 t amattioni P38-mapk can directly phosphorylate and inhibit the activities of caspase-8 SIGNOR-122103 0.571 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 19920149 t gcesareni Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 SIGNOR-161766 0.572 SIGNOR-TA TNF-alpha Signaling MAPK14 protein Q16539 UNIPROT CASP3 protein P42574 UNIPROT down-regulates phosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 14970175 t gcesareni Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response. SIGNOR-122099 0.766 SIGNOR-TA TNF-alpha Signaling BAX protein Q07812 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 SIGNOR-TA TNF-alpha Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.71 SIGNOR-TA TNF-alpha Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 0.71 SIGNOR-TA TNF-alpha Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-TA TNF-alpha Signaling RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. SIGNOR-108257 0.427 SIGNOR-TA TNF-alpha Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.71 SIGNOR-TA TNF-alpha Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.57 SIGNOR-TA TNF-alpha Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 SIGNOR-236376 0.712 SIGNOR-TA TNF-alpha Signaling CASP3 protein P42574 UNIPROT PARP1 factor protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 t amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-116178 0.767 SIGNOR-TA TNF-alpha Signaling TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 t gcesareni Rip1 is known to directly interact with traf2 SIGNOR-245032 0.889 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.935 SIGNOR-TA TNF-alpha Signaling PARP1 factor protein P09874 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 t lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. SIGNOR-179446 0.864 SIGNOR-TA TNF-alpha Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-TA TNF-alpha Signaling FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.784 SIGNOR-TA TNF-alpha Signaling RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 12887920 t amattioni Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex SIGNOR-104255 0.906 SIGNOR-TA TNF-alpha Signaling MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.682 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45366 0.612 SIGNOR-TA TNF-alpha Signaling TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 9774977 t lperfetto Traf2 is a strong activator of ask1 SIGNOR-60747 0.726 SIGNOR-TA TNF-alpha Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 0.71 SIGNOR-TA TNF-alpha Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-TA TNF-alpha Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-244982 0.736 SIGNOR-TA TNF-alpha Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 23070005 t miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. SIGNOR-199091 0.923 SIGNOR-TA TNF-alpha Signaling IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-TA TNF-alpha Signaling MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51199 0.682 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 t lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45373 0.612 SIGNOR-TA TNF-alpha Signaling FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.929 SIGNOR-TA TNF-alpha Signaling TNF extracellular protein P01375 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.923 SIGNOR-TA TNF-alpha Signaling BAG4 protein O95429 UNIPROT TNFRSF1A receptor protein P19438 UNIPROT down-regulates activity binding 10090 BTO:0000801 12748303 t gcesareni It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation SIGNOR-245022 0.629 SIGNOR-TA TNF-alpha Signaling BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 t amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. SIGNOR-73902 0.817 SIGNOR-TA TNF-alpha Signaling TNFRSF1A receptor protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 t lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. SIGNOR-32739 0.799 SIGNOR-TA TNF-alpha Signaling RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 21525013 t amattioni Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex SIGNOR-173432 0.906 SIGNOR-TA TNF-alpha Signaling TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 10688666 t lperfetto Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide SIGNOR-75334 0.726 SIGNOR-TA TNF-alpha Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 SIGNOR-27973 0.57 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11959862 t amattioni Activation of mkk7 by ask1 SIGNOR-117264 0.572 SIGNOR-TA TNF-alpha Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR JUN factor protein P05412 UNIPROT up-regulates binding 9606 18174238 t lperfetto Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment SIGNOR-216337 0.58 SIGNOR-TA TNF-alpha Signaling CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 t amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity SIGNOR-59655 0.872 SIGNOR-TA TNF-alpha Signaling JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 t lperfetto Tradd recruits fadd SIGNOR-177958 0.775 SIGNOR-TA TNF-alpha Signaling FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-173429 0.784 SIGNOR-TA TNF-alpha Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Inflammation phenotypesList phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 f gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. SIGNOR-245039 0.7 SIGNOR-TA TNF-alpha Signaling MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 8974401 t lperfetto ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively SIGNOR-226672 0.578 SIGNOR-TA TNF-alpha Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.71 SIGNOR-TA TNF-alpha Signaling NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-TA TNF-alpha Signaling NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-TA TNF-alpha Signaling RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 t gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation SIGNOR-245026 0.658 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.864 SIGNOR-TA TNF-alpha Signaling TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 t lperfetto The strong interaction between tradd and fadd occurs via their death domains. SIGNOR-39951 0.775 SIGNOR-TA TNF-alpha Signaling NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. SIGNOR-245043 0.7 SIGNOR-TA TNF-alpha Signaling MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 SIGNOR-236380 0.712 SIGNOR-TA TNF-alpha Signaling MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 t amattioni Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183). SIGNOR-83736 0.682 SIGNOR-TA TNF-alpha Signaling MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51211 0.706 SIGNOR-TA TNF-alpha Signaling CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.707 SIGNOR-TA TNF-alpha Signaling MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.736 SIGNOR-TC Thyroid cancer PTEN protein P60484 UNIPROT PIP3 receptor smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 t lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. SIGNOR-228145 0.8 SIGNOR-TC Thyroid cancer TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.838 SIGNOR-TC Thyroid cancer CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 t miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade SIGNOR-251986 0.2 SIGNOR-TC Thyroid cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19861538 t miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. SIGNOR-251989 0.2 SIGNOR-TC Thyroid cancer RET receptor protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 t gcesareni We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret. SIGNOR-36902 0.639 SIGNOR-TC Thyroid cancer PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-TC Thyroid cancer Ionizing radiation extracellular stimulus SIGNOR-ST16 SIGNOR CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR up-regulates 9606 23128507 f miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents SIGNOR-251999 0.7 SIGNOR-TC Thyroid cancer SLC5A5 receptor protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates activity chemical activation 9606 14623893 t miannu Iodide is an essential element in thyroid physiology as a critical component of thyroxine and triiodothyronine molecules and a key regulator of thyroid gland function. The first step in iodide metabolism is represented by thyroid trapping, which is achieved by an active, energy-dependent transport process across the basolateral plasma membrane of the thyrocytes. The protein responsible for this process, the sodium/iodide symporter (NIS),1 is an intrinsic plasma membrane protein that mediates active transport of I- in the thyroid, lactating mammary gland, stomach, and salivary glands SIGNOR-251996 0.8 SIGNOR-TC Thyroid cancer SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236363 0.761 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. SIGNOR-251550 0.7 SIGNOR-TC Thyroid cancer TGFBR1 receptor protein P36897 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 10090 BTO:0005065 17673906 t lperfetto We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases. SIGNOR-227503 0.525 SIGNOR-TC Thyroid cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-TC Thyroid cancer TPO protein P07202 UNIPROT TG protein P01266 UNIPROT up-regulates activity catalytic activity 9606 23349248 t miannu After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259914 0.528 SIGNOR-TC Thyroid cancer KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-156906 0.872 SIGNOR-TC Thyroid cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-141647 0.82 SIGNOR-TC Thyroid cancer Ionizing radiation extracellular stimulus SIGNOR-ST16 SIGNOR ELE1-RET fusion protein SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 f miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents SIGNOR-251984 0.7 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-244222 0.2 SIGNOR-TC Thyroid cancer iodide smallmolecule CHEBI:16382 ChEBI TPO protein P07202 UNIPROT up-regulates activity chemical activation 9606 BTO:0004708 23349248 t miannu After transport through the apical membrane, Iodide is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-268139 0.8 SIGNOR-TC Thyroid cancer SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 t lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. SIGNOR-236366 0.965 SIGNOR-TC Thyroid cancer CTNNB1 protein P35222 UNIPROT PPARG factor protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 0.56 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244160 0.2 SIGNOR-TC Thyroid cancer PPARG factor protein P37231 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity 9606 23128507 t PAX8-PPARγ fusion protein miannu The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway. SIGNOR-251997 0.476 SIGNOR-TC Thyroid cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-175256 0.82 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT TGFB1 extracellular protein P01137 UNIPROT up-regulates quantity relocalization 9606 19861538 f miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. SIGNOR-251987 0.252 SIGNOR-TC Thyroid cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG factor protein P37231 UNIPROT up-regulates quantity by expression phosphorylation 10090 BTO:0000011 12270934 t lperfetto Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression. SIGNOR-235334 0.2 SIGNOR-TC Thyroid cancer TG protein P01266 UNIPROT Thyroid_hormonogenesis phenotypesList phenotype SIGNOR-PH110 SIGNOR up-regulates 9606 BTO:0004710 30886364 f miannu In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites. SIGNOR-259915 0.7 SIGNOR-TC Thyroid cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-TC Thyroid cancer MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-TC Thyroid cancer CTNNB1 protein P35222 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.737 SIGNOR-TC Thyroid cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-TC Thyroid cancer ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 SIGNOR-TC Thyroid cancer ELE1-RET fusion protein SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 t miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade SIGNOR-251985 0.2 SIGNOR-TC Thyroid cancer SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 SIGNOR-TC Thyroid cancer PPARG factor protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20303941 f gcesareni The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. SIGNOR-164516 0.56 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-TC Thyroid cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244156 0.2 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249645 0.2 SIGNOR-TC Thyroid cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-TC Thyroid cancer SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-235881 0.965 SIGNOR-TC Thyroid cancer TSHB extracellular protein P01222 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 t miannu I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane SIGNOR-251995 0.395 SIGNOR-TC Thyroid cancer SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-122075 0.82 SIGNOR-TC Thyroid cancer GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-TC Thyroid cancer PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-TC Thyroid cancer iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 23349248 t miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259913 0.8 SIGNOR-TC Thyroid cancer FOXO3 factor protein O43524 UNIPROT Apoptosis phenotypesList phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-217887 0.7 SIGNOR-TC Thyroid cancer RET receptor protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 12738763 t lperfetto Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1. SIGNOR-235863 0.2 SIGNOR-TC Thyroid cancer TSHB extracellular protein P01222 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT up-regulates quantity by stabilization 9606 14623893 f miannu Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane SIGNOR-251994 0.395 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249646 0.2 SIGNOR-TC Thyroid cancer BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 factor protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 SIGNOR-TC Thyroid cancer PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-244225 0.2 SIGNOR-TC Thyroid cancer PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-TC Thyroid cancer AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 SIGNOR-TC Thyroid cancer TGFB1 extracellular protein P01137 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 f miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression SIGNOR-259912 0.2 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102511 0.798 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function SIGNOR-251393 0.597 SIGNOR-TCA T cell activation 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 t lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), SIGNOR-244469 0.73 SIGNOR-TCA T cell activation GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-TCA T cell activation PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 t lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. SIGNOR-58313 0.8 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.784 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247018 0.763 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck SIGNOR-249375 0.597 SIGNOR-TCA T cell activation BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-TCA T cell activation LAT receptor protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.801 SIGNOR-TCA T cell activation Class I MHC:Antigen extracellular complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT up-regulates activity binding 9606 21954283 t scontino Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands. SIGNOR-267991 0.2 SIGNOR-TCA T cell activation PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C. SIGNOR-248936 0.328 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102507 0.798 SIGNOR-TCA T cell activation NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. SIGNOR-236321 0.595 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42972 0.798 SIGNOR-TCA T cell activation LAT receptor protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-252734 0.401 SIGNOR-TCA T cell activation PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-TCA T cell activation SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-59472 0.886 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT CD28 receptor protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-45524 0.745 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251395 0.597 SIGNOR-TCA T cell activation Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 factor protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252323 0.817 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr145 PVEDDADyEPPPSND 9606 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102515 0.798 SIGNOR-TCA T cell activation BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 t lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation SIGNOR-244934 0.277 SIGNOR-TCA T cell activation IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity phosphorylation 10090 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259932 0.2 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251382 0.744 SIGNOR-TCA T cell activation HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-TCA T cell activation LAT receptor protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000661 10811803 t Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding; SIGNOR-251521 0.797 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247030 0.763 SIGNOR-TCA T cell activation PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 12876277 t lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. SIGNOR-244924 0.559 SIGNOR-TCA T cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 SIGNOR-TCA T cell activation HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-TCA T cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 9651347 t gcesareni Our results indicate that ca2+ ions not only anchor the protein to membrane surfaces but also induce conformational changes resulting in pkc activation. SIGNOR-58506 0.8 SIGNOR-TCA T cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 t lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 0.8 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. SIGNOR-149182 0.749 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.784 SIGNOR-TCA T cell activation PTPRC receptor protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 10090 BTO:0000782 17719247 t CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity. SIGNOR-259933 0.79 SIGNOR-TCA T cell activation LAT receptor protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 23150273 t Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling SIGNOR-251520 0.797 SIGNOR-TCA T cell activation FYN protein P06241 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-148931 0.737 SIGNOR-TCA T cell activation CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 11231575 t Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments. SIGNOR-251519 0.63 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244584 0.2 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 t miannu P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1. SIGNOR-250267 0.364 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244588 0.2 SIGNOR-TCA T cell activation PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165220 0.694 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 t lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. SIGNOR-46859 0.798 SIGNOR-TCA T cell activation PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165216 0.694 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-43659 0.597 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 t lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. SIGNOR-244421 0.73 SIGNOR-TCA T cell activation PTPRC receptor protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 t Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity SIGNOR-248350 0.79 SIGNOR-TCA T cell activation PRKCA protein P17252 UNIPROT NFATC1 factor protein O95644 UNIPROT down-regulates activity phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. SIGNOR-249175 0.393 SIGNOR-TCA T cell activation CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT up-regulates activity binding 9534 1423621 t We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction. SIGNOR-252304 0.681 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 9047237 t lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. SIGNOR-46855 0.798 SIGNOR-TCA T cell activation CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 t gcesareni P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity. SIGNOR-20371 0.512 SIGNOR-TCA T cell activation HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-TCA T cell activation PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 t gcesareni Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199. SIGNOR-99310 0.535 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr200 SMESIDDyVNVPESG 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247026 0.763 SIGNOR-TCA T cell activation PTPRC receptor protein P08575 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 t Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity SIGNOR-248351 0.79 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 16938345 t gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. SIGNOR-149186 0.749 SIGNOR-TCA T cell activation calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell). SIGNOR-198822 0.8 SIGNOR-TCA T cell activation FYN protein P06241 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. SIGNOR-149174 0.737 SIGNOR-TCA T cell activation PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-169690 0.694 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782 7642520 t lperfetto When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck SIGNOR-30429 0.597 SIGNOR-TCA T cell activation PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 21079800 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-169694 0.694 SIGNOR-TCA T cell activation ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotypesList phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 f lperfetto The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension. SIGNOR-251511 0.7 SIGNOR-TCA T cell activation IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-TCA T cell activation PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23140367 t miannu Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-251558 0.8 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT CD28 receptor protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-198755 0.745 SIGNOR-TCA T cell activation PTPRC receptor protein P08575 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 t On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction. SIGNOR-248352 0.719 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251396 0.597 SIGNOR-TCA T cell activation CD28 receptor protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation SIGNOR-202706 0.69 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 t We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. SIGNOR-251392 0.597 SIGNOR-TCA T cell activation FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 t lperfetto P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation SIGNOR-46851 0.744 SIGNOR-TCA T cell activation Class I MHC:Antigen extracellular complex SIGNOR-C426 SIGNOR TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 t scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. SIGNOR-267993 0.2 SIGNOR-TCA T cell activation IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-TCA T cell activation Class II MHC:Antigen extracellular complex SIGNOR-C429 SIGNOR TCR receptor complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 t scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. SIGNOR-267992 0.2 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 t lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. SIGNOR-226628 0.597 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors SIGNOR-249374 0.563 SIGNOR-TCA T cell activation CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259935 0.345 SIGNOR-TCA T cell activation PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 t gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) SIGNOR-243274 0.8 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42956 0.798 SIGNOR-TCA T cell activation GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-TCA T cell activation ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252353 0.784 SIGNOR-TCA T cell activation NFATC1 factor protein O95644 UNIPROT T_cell_activation extracellular phenotype SIGNOR-PH73 SIGNOR up-regulates activity 10358178 f The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. SIGNOR-252344 0.7 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42960 0.798 SIGNOR-TCA T cell activation CD28 receptor protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7737275 t fspada In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase. SIGNOR-32509 0.69 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr255 EEEGAPDyENLQELN 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247034 0.763 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 t lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-244938 0.277 SIGNOR-TCA T cell activation AP1 factor complex SIGNOR-C154 SIGNOR CD3 complex SIGNOR-C432 SIGNOR up-regulates activity binding 9606 16473826 t scontino When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery. SIGNOR-267994 0.326 SIGNOR-TCA T cell activation BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-TCA T cell activation MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-TCA T cell activation PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126066 0.387 SIGNOR-TCA T cell activation AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-TCA T cell activation AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.639 SIGNOR-TCA T cell activation NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR up-regulates activity phosphorylation 9606 8626561 t The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex SIGNOR-252305 0.63 SIGNOR-TCA T cell activation NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-TCA T cell activation NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-TCA T cell activation PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42976 0.798 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 t lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function SIGNOR-42968 0.798 SIGNOR-TCA T cell activation CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-252337 0.568 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251381 0.744 SIGNOR-TCA T cell activation IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-TCA T cell activation BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 t miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. SIGNOR-251988 0.774 SIGNOR-TCA T cell activation LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-67443 0.597 SIGNOR-TCA T cell activation IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-TCA T cell activation PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-TCA T cell activation ZAP70 protein P43403 UNIPROT LAT receptor protein O43561 UNIPROT up-regulates activity phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247022 0.763 SIGNOR-TCA T cell activation Class II MHC:Antigen extracellular complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT up-regulates activity binding 9606 31001252 t scontino Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens SIGNOR-267990 0.2 SIGNOR-TCA T cell activation 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 12629049 t Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated. SIGNOR-251559 0.8 SIGNOR-TEAT Translation elongation and termination HARS1 protein P12081 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270490 0.8 SIGNOR-TEAT Translation elongation and termination Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR down-regulates activity binding 9606 28368393 t miannu The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism. SIGNOR-270817 0.2 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270390 0.8 SIGNOR-TEAT Translation elongation and termination YARS1 protein P54577 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity chemical modification 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270522 0.8 SIGNOR-TEAT Translation elongation and termination NARS1 protein O43776 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270456 0.8 SIGNOR-TEAT Translation elongation and termination alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270808 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269502 0.8 SIGNOR-TEAT Translation elongation and termination Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR protein polypeptide chain smallmolecule CHEBI:16541 ChEBI up-regulates quantity chemical modification 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270818 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269504 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269514 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270430 0.8 SIGNOR-TEAT Translation elongation and termination TARS1 protein P26639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270506 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269508 0.8 SIGNOR-TEAT Translation elongation and termination EIF3_complex complex SIGNOR-C401 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity binding 9606 16920360 t miannu EIF3 binds 40S and inhibits the association of 60S. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis. SIGNOR-266401 0.591 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269511 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270809 0.2 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269510 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269516 0.8 SIGNOR-TEAT Translation elongation and termination CARS1 protein P49589 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270474 0.8 SIGNOR-TEAT Translation elongation and termination EEF2 protein P13639 UNIPROT 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR up-regulates activity binding 9606 14709557 t lperfetto In mammalian cells, peptide chain elongation requires two main elongation factors, eEF1A and eEF2. The latter mediates the translocation step of elongation in which the ribosome moves by the equivalent of one codon relative to the mRNA, and the peptidyl-tRNA shifts from the A- into the P-site on the ribosomend eEF2. SIGNOR-269397 0.2 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269520 0.8 SIGNOR-TEAT Translation elongation and termination GARS1 protein P41250 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270482 0.8 SIGNOR-TEAT Translation elongation and termination EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1 protein P68104 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269387 0.918 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269509 0.8 SIGNOR-TEAT Translation elongation and termination 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269171 0.2 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269507 0.8 SIGNOR-TEAT Translation elongation and termination WARS1 protein P23381 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270514 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270398 0.8 SIGNOR-TEAT Translation elongation and termination AARS1 protein P49588 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270447 0.8 SIGNOR-TEAT Translation elongation and termination ABCE1 protein P61221 UNIPROT 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR down-regulates quantity by destabilization binding 9606 28368393 t miannu The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism. SIGNOR-270816 0.2 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270414 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269521 0.8 SIGNOR-TEAT Translation elongation and termination 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR peptide smallmolecule CHEBI:16670 ChEBI up-regulates quantity chemical modification 9606 20025795 t miannu In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer SIGNOR-270811 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270382 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270422 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270366 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269506 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269505 0.8 SIGNOR-TEAT Translation elongation and termination VARS1 protein P26640 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270530 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269518 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270406 0.8 SIGNOR-TEAT Translation elongation and termination SARS1 protein P49591 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270498 0.8 SIGNOR-TEAT Translation elongation and termination Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270374 0.8 SIGNOR-TEAT Translation elongation and termination peptide smallmolecule CHEBI:16670 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR up-regulates activity binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270815 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269512 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269513 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269519 0.8 SIGNOR-TEAT Translation elongation and termination GTP smallmolecule CHEBI:15996 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270812 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269515 0.8 SIGNOR-TEAT Translation elongation and termination messenger RNA smallmolecule CHEBI:33699 ChEBI 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269172 0.8 SIGNOR-TEAT Translation elongation and termination Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270442 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR up-regulates activity binding 9606 20025795 t miannu The work cycle during which a new amino acid is added to the growing polypeptide chain, referred to as elongation cycle, is a repetitive multistep process encompassing aminoacyl-tRNA (aa-tRNA) selection, peptide bond formation, and mRNA–tRNA translocation (Fig. 1). In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer SIGNOR-270810 0.2 SIGNOR-TEAT Translation elongation and termination 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269170 0.2 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269517 0.8 SIGNOR-TEAT Translation elongation and termination EEF1A1 protein P68104 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269503 0.8 SIGNOR-TGFb TGF-beta Signaling FKBP1A protein P62942 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 BTO:0005493 8756725 t lperfetto Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands SIGNOR-236142 0.844 SIGNOR-TGFb TGF-beta Signaling SKIL factor protein P12757 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253302 0.837 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR2 receptor protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-253265 0.2 SIGNOR-TGFb TGF-beta Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.57 SIGNOR-TGFb TGF-beta Signaling TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 0.703 SIGNOR-TGFb TGF-beta Signaling SMAD6 protein O43541 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity binding 10116 11737269 t lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. SIGNOR-235571 0.546 SIGNOR-TGFb TGF-beta Signaling ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity relocalization 9606 20515759 t lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-165786 0.904 SIGNOR-TGFb TGF-beta Signaling MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0001939 15520018 t miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. SIGNOR-250113 0.558 SIGNOR-TGFb TGF-beta Signaling SMAD7 protein O15105 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 20663871 t lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. SIGNOR-167163 0.781 SIGNOR-TGFb TGF-beta Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.71 SIGNOR-TGFb TGF-beta Signaling MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-TGFb TGF-beta Signaling MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10116 14512875 t lperfetto P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4. SIGNOR-236136 0.558 SIGNOR-TGFb TGF-beta Signaling SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256286 0.586 SIGNOR-TGFb TGF-beta Signaling TGFB2 extracellular protein P61812 UNIPROT TGFBR2 receptor protein P37173 UNIPROT up-regulates binding 9606 11157754 t gcesareni We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor SIGNOR-104795 0.743 SIGNOR-TGFb TGF-beta Signaling JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 0.2 SIGNOR-TGFb TGF-beta Signaling SMAD6 protein O43541 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto SMAD6 functions as a negative regulator of the TGFB and BMP signaling pathways by interacting with other SMADs and/or TBRI. SIGNOR-64079 0.729 SIGNOR-TGFb TGF-beta Signaling SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.701 SIGNOR-TGFb TGF-beta Signaling SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260440 0.7 SIGNOR-TGFb TGF-beta Signaling TGFBR2 receptor protein P37173 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-245093 0.547 SIGNOR-TGFb TGF-beta Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 0.728 SIGNOR-TGFb TGF-beta Signaling ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-232126 0.852 SIGNOR-TGFb TGF-beta Signaling ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 20515759 t lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. SIGNOR-59145 0.852 SIGNOR-TGFb TGF-beta Signaling SKIL factor protein P12757 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253303 0.834 SIGNOR-TGFb TGF-beta Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.71 SIGNOR-TGFb TGF-beta Signaling ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. SIGNOR-62874 0.852 SIGNOR-TGFb TGF-beta Signaling SKI factor protein P12755 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253301 0.761 SIGNOR-TGFb TGF-beta Signaling MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 0.728 SIGNOR-TGFb TGF-beta Signaling SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 22298955 t Create a non-functional complex with smad4 and competes with R-smad. lperfetto On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation. SIGNOR-195648 0.552 SIGNOR-TGFb TGF-beta Signaling SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR Fibrosis phenotypesList phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260441 0.7 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.82 SIGNOR-TGFb TGF-beta Signaling JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137627 0.2 SIGNOR-TGFb TGF-beta Signaling SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR ATF2 factor protein P15336 UNIPROT up-regulates activity binding 9606 10085140 t lperfetto Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. SIGNOR-65583 0.577 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-236119 0.44 SIGNOR-TGFb TGF-beta Signaling SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.628 SIGNOR-TGFb TGF-beta Signaling MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 t lperfetto Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). SIGNOR-83729 0.736 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 t lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm SIGNOR-253260 0.2 SIGNOR-TGFb TGF-beta Signaling TGFB2 extracellular protein P61812 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates binding 9606 22326956 t miannu Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family. SIGNOR-196025 0.734 SIGNOR-TGFb TGF-beta Signaling TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity binding 9606 22703233 t lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-249548 0.838 SIGNOR-TGFb TGF-beta Signaling MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.71 SIGNOR-TGFb TGF-beta Signaling MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236110 0.736 SIGNOR-TGFb TGF-beta Signaling JNK proteinfamily SIGNOR-PF15 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005493 10601313 t lperfetto JNK-mediated phosphorylation of Smad3 outside the -SSXS motif enhances Smad3 nuclear translocation and potentiates transcriptional activation independent of Smad3 phosphorylation by T_RI. SIGNOR-236113 0.2 SIGNOR-TGFb TGF-beta Signaling ATF2 factor protein P15336 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 f Luana ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. SIGNOR-261324 0.7 SIGNOR-TGFb TGF-beta Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.748 SIGNOR-TGFb TGF-beta Signaling AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-TGFb TGF-beta Signaling CBP/p300 complex SIGNOR-C6 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. To identify the specific lysine residue acetylated by p300, lys19, and lys20 in smad2(fl) were mutated individually and subjected to p300-mediated acetylation following expression in 293t cells. Mutation of lys19 blocked the p300-mediated acetylation of smad2(fl), whereas mutation of lys20 had no effect (fig. 2b), suggesting that lys19 is the preferred site for p300-mediated acetylation of smad2(fl). SIGNOR-235899 0.644 SIGNOR-TGFb TGF-beta Signaling MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.748 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.82 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 t lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. SIGNOR-253261 0.2 SIGNOR-TGFb TGF-beta Signaling JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 t miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity SIGNOR-253340 0.812 SIGNOR-TGFb TGF-beta Signaling CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKGEQNGQ 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3. SIGNOR-236126 0.68 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 t gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors SIGNOR-241918 0.44 SIGNOR-TGFb TGF-beta Signaling SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 9892110 t lperfetto Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3 SIGNOR-64071 0.475 SIGNOR-TGFb TGF-beta Signaling SMAD7 protein O15105 UNIPROT SMURF proteinfamily SIGNOR-PF29 SIGNOR up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-253258 0.893 SIGNOR-TGFb TGF-beta Signaling SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256287 0.586 SIGNOR-TGFb TGF-beta Signaling SMAD6 protein O43541 UNIPROT TGFBR1 receptor protein P36897 UNIPROT down-regulates activity binding 9606 20663871 t lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. SIGNOR-167160 0.729 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD4 protein Q13485 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181 15817471 t In the presence of smad6 or smad7 acting as adaptors lperfetto Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes. SIGNOR-253259 0.2 SIGNOR-TGFb TGF-beta Signaling SKI factor protein P12755 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-253300 0.768 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR1 receptor protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation SIGNOR-253264 0.2 SIGNOR-TGFb TGF-beta Signaling CDKN2B protein P42772 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 f The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. SIGNOR-259407 0.7 SIGNOR-TGFb TGF-beta Signaling SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 0.701 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 t lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex SIGNOR-62868 0.613 SIGNOR-TGFb TGF-beta Signaling MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.692 SIGNOR-TGFb TGF-beta Signaling TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-TGFb TGF-beta Signaling TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 10973958 t lperfetto The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released. SIGNOR-249549 0.82 SIGNOR-TGFb TGF-beta Signaling MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. SIGNOR-250112 0.558 SIGNOR-TGFb TGF-beta Signaling MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 t lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 0.48 SIGNOR-TGFb TGF-beta Signaling SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 t lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. SIGNOR-253263 0.2 SIGNOR-TGFb TGF-beta Signaling MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 t lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 SIGNOR-27973 0.57 SIGNOR-TGFb TGF-beta Signaling CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation 9606 9865691 t lperfetto The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3. SIGNOR-227553 0.68 SIGNOR-THM Thyroid Hormone Metabolism UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267482 0.388 SIGNOR-THM Thyroid Hormone Metabolism TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-THM Thyroid Hormone Metabolism 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267038 0.8 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity chemical modification 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266957 0.8 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT TG protein P01266 UNIPROT up-regulates activity catalytic activity 9606 23349248 t miannu After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259914 0.528 SIGNOR-THM Thyroid Hormone Metabolism CREB1 factor protein P16220 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 34751390 t scontino CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription. SIGNOR-267137 0.273 SIGNOR-THM Thyroid Hormone Metabolism calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 t lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 SIGNOR-266950 0.8 SIGNOR-THM Thyroid Hormone Metabolism PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 t gcesareni The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex, SIGNOR-166368 0.265 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. SIGNOR-267619 0.7 SIGNOR-THM Thyroid Hormone Metabolism GATA2 factor protein P23769 UNIPROT TRH extracellular protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 33201916 t scontino The rat prepro-TRH gene is activated by GATA2. SIGNOR-267259 0.268 SIGNOR-THM Thyroid Hormone Metabolism DIO2 protein Q92813 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266953 0.8 SIGNOR-THM Thyroid Hormone Metabolism CREBBP protein Q92793 UNIPROT IRF9 factor protein Q00978 UNIPROT up-regulates activity acetylation Lys81 TGGPAVWkTRLRCAL 9606 BTO:0000007 17923090 t lperfetto CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel). SIGNOR-217787 0.369 SIGNOR-THM Thyroid Hormone Metabolism GATA2 factor protein P23769 UNIPROT TSHB extracellular protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 9305891 t scontino Pit-1, is necessary but not sufficient to allow basal transcription of the mTSHβ gene.The analysis of the mTSHβ gene described in this report provides evidence for the participation of a zinc finger factor, GATA-2, with a POU homeodomain partner, Pit-1, on a such a composite element.In summary, we have shown the requirement for at least two different classes of transcription factors to regulate mTSHβ gene expression. Both GATA-2 and Pit-1 can bind independently to the P1 region of the promoter, form a heteromeric complex with DNA, and functionally synergize to activate TSHβ promoter activity. SIGNOR-267253 0.406 SIGNOR-THM Thyroid Hormone Metabolism GNAS protein P63092 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 t gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. SIGNOR-252678 0.368 SIGNOR-THM Thyroid Hormone Metabolism mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 19593385 f lperfetto Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. SIGNOR-235349 0.7 SIGNOR-THM Thyroid Hormone Metabolism UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267483 0.2 SIGNOR-THM Thyroid Hormone Metabolism PAX8 factor protein Q06710 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 t scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. SIGNOR-267277 0.415 SIGNOR-THM Thyroid Hormone Metabolism 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267037 0.8 SIGNOR-THM Thyroid Hormone Metabolism SMAD3 protein P84022 UNIPROT PAX8 factor protein Q06710 UNIPROT down-regulates activity binding 9606 14623893 t miannu DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3. SIGNOR-251992 0.374 SIGNOR-THM Thyroid Hormone Metabolism PLCB1 protein Q9NQ66 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256496 0.8 SIGNOR-THM Thyroid Hormone Metabolism DIO1 protein P49895 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266954 0.8 SIGNOR-THM Thyroid Hormone Metabolism CREBBP protein Q92793 UNIPROT LHX3 factor protein Q9UBR4 UNIPROT up-regulates activity binding 9606 10931853 t scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter. SIGNOR-267206 0.2 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Fatty_Acid_Biosynthesis phenotypesList phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. SIGNOR-267488 0.7 SIGNOR-THM Thyroid Hormone Metabolism UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267481 0.388 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267040 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267276 0.8 SIGNOR-THM Thyroid Hormone Metabolism GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-37149 0.76 SIGNOR-THM Thyroid Hormone Metabolism SLC5A5 receptor protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity relocalization 10116 28192058 t scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  SIGNOR-266960 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB receptor protein P10828 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267254 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267035 0.8 SIGNOR-THM Thyroid Hormone Metabolism THR proteinfamily SIGNOR-PF84 SIGNOR GATA2 factor protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267275 0.2 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA receptor protein P10827 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267255 0.8 SIGNOR-THM Thyroid Hormone Metabolism IFNG extracellular protein P01579 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267487 0.2 SIGNOR-THM Thyroid Hormone Metabolism TRHR receptor protein P34981 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 t scontino Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267201 0.457 SIGNOR-THM Thyroid Hormone Metabolism CREBBP protein Q92793 UNIPROT POU1F1 factor protein P28069 UNIPROT up-regulates activity binding 9606 BTO:0001379 10931853 t scontino  We and others have recently shown that CBP can constitutively bind to Pit-1 and synergistically activate transcription of promoters containing Pit-1 DNA-binding sites. SIGNOR-267204 0.389 SIGNOR-THM Thyroid Hormone Metabolism TGFB1 extracellular protein P01137 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 0.838 SIGNOR-THM Thyroid Hormone Metabolism WWTR1 factor protein Q9GZV5 UNIPROT PAX8 factor protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. SIGNOR-182253 0.31 SIGNOR-THM Thyroid Hormone Metabolism DIO1 protein P49895 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266945 0.8 SIGNOR-THM Thyroid Hormone Metabolism PAX8 factor protein Q06710 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 t miannu Pax8 has an essential role in thyroid organogenesis and differentiation, being the main mediator of thyroid gene transcription, including the NIS gene. SIGNOR-251990 0.425 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267039 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. SIGNOR-267491 0.7 SIGNOR-THM Thyroid Hormone Metabolism POU1F1 factor protein P28069 UNIPROT TSHB extracellular protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 t scontino CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites. SIGNOR-267205 0.456 SIGNOR-THM Thyroid Hormone Metabolism PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 t miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. SIGNOR-263653 0.2 SIGNOR-THM Thyroid Hormone Metabolism 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267031 0.8 SIGNOR-THM Thyroid Hormone Metabolism PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 t miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. SIGNOR-256497 0.8 SIGNOR-THM Thyroid Hormone Metabolism AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO factor proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252826 0.909 SIGNOR-THM Thyroid Hormone Metabolism CREBBP protein Q92793 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates binding 9606 9829964 t gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62260 0.939 SIGNOR-THM Thyroid Hormone Metabolism 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i. SIGNOR-179291 0.8 SIGNOR-THM Thyroid Hormone Metabolism TSHR receptor protein P16473 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 32698392 t scontino Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations SIGNOR-267138 0.542 SIGNOR-THM Thyroid Hormone Metabolism TSH extracellular complex SIGNOR-C412 SIGNOR TSHR receptor protein P16473 UNIPROT up-regulates activity binding 9606 BTO:0001379 25905363 t scontino The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland. SIGNOR-267048 0.558 SIGNOR-THM Thyroid Hormone Metabolism PAX8 factor protein Q06710 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11786384 t miannu The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression. SIGNOR-251998 0.478 SIGNOR-THM Thyroid Hormone Metabolism CAMK4 protein Q16566 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation Ser302 PQLASKQsMVNSLPT BTO:0000938 11970865 t llicata Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301. SIGNOR-250710 0.622 SIGNOR-THM Thyroid Hormone Metabolism SLC16A2 receptor protein P36021 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI down-regulates quantity relocalization 9606 28153798 t scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. SIGNOR-267139 0.8 SIGNOR-THM Thyroid Hormone Metabolism mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0002314 25047835 f Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. SIGNOR-256273 0.7 SIGNOR-THM Thyroid Hormone Metabolism WWTR1 factor protein Q9GZV5 UNIPROT NKX2-1 factor protein P43699 UNIPROT up-regulates binding 9606 BTO:0000887 16397409 t gcesareni Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant. SIGNOR-143472 0.437 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266940 0.8 SIGNOR-THM Thyroid Hormone Metabolism GNA11 protein P29992 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 27515033 t scontino TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267203 0.603 SIGNOR-THM Thyroid Hormone Metabolism PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. SIGNOR-254950 0.785 SIGNOR-THM Thyroid Hormone Metabolism FOXO factor proteinfamily SIGNOR-PF27 SIGNOR Adipogenesis phenotypesList phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 18423396 f fspada Akt1/pkbalpha was found to be the major regulator of phosphorylation and nuclear export offoxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. SIGNOR-252911 0.7 SIGNOR-THM Thyroid Hormone Metabolism TRHR receptor protein P34981 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 23248581 t scontino TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ). SIGNOR-267202 0.464 SIGNOR-THM Thyroid Hormone Metabolism TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 t miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 0.806 SIGNOR-THM Thyroid Hormone Metabolism TG protein P01266 UNIPROT Colloid phenotype SIGNOR-PH185 SIGNOR up-regulates 9606 24251883 f scontino The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation. SIGNOR-267135 0.7 SIGNOR-THM Thyroid Hormone Metabolism GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.611 SIGNOR-THM Thyroid Hormone Metabolism CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates activity phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. SIGNOR-250718 0.6 SIGNOR-THM Thyroid Hormone Metabolism DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266942 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI Fatty_Acid_Biosynthesis phenotypesList phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. SIGNOR-267489 0.7 SIGNOR-THM Thyroid Hormone Metabolism SLC5A5 receptor protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 10116 28192058 t scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  SIGNOR-266961 0.8 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267041 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 12746313 t scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. SIGNOR-266946 0.8 SIGNOR-THM Thyroid Hormone Metabolism TSHR receptor protein P16473 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 25878058 t scontino The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor. SIGNOR-267136 0.647 SIGNOR-THM Thyroid Hormone Metabolism AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266943 0.8 SIGNOR-THM Thyroid Hormone Metabolism TNF extracellular protein P01375 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267485 0.2 SIGNOR-THM Thyroid Hormone Metabolism CALM1 protein P0DP23 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 t gcesareni The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. SIGNOR-61922 0.826 SIGNOR-THM Thyroid Hormone Metabolism NKX2-1 factor protein P43699 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 t scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. SIGNOR-267278 0.393 SIGNOR-THM Thyroid Hormone Metabolism TRH extracellular protein P20396 UNIPROT TRHR receptor protein P34981 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 t scontino When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH. SIGNOR-267200 0.754 SIGNOR-THM Thyroid Hormone Metabolism IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267034 0.8 SIGNOR-THM Thyroid Hormone Metabolism 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 f gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. SIGNOR-179288 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. SIGNOR-267620 0.7 SIGNOR-THM Thyroid Hormone Metabolism TGFB1 extracellular protein P01137 UNIPROT SLC5A5 receptor protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 f miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression SIGNOR-259912 0.2 SIGNOR-THM Thyroid Hormone Metabolism iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266958 0.8 SIGNOR-THM Thyroid Hormone Metabolism SLC16A2 receptor protein P36021 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity relocalization 9606 28153798 t scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. SIGNOR-267140 0.8 SIGNOR-THM Thyroid Hormone Metabolism ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-THM Thyroid Hormone Metabolism TPO protein P07202 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity chemical modification 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-267030 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO2 protein Q92813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 29892818 f scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-267281 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. SIGNOR-267492 0.7 SIGNOR-THM Thyroid Hormone Metabolism CAMK4 protein Q16566 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0001271 12835716 t lperfetto Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB. SIGNOR-102722 0.7 SIGNOR-THM Thyroid Hormone Metabolism LHX3 factor protein Q9UBR4 UNIPROT CGA extracellular protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 t scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation. SIGNOR-267207 0.401 SIGNOR-THM Thyroid Hormone Metabolism CGA extracellular protein P01215 UNIPROT TSH extracellular complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 t scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. SIGNOR-267046 0.665 SIGNOR-THM Thyroid Hormone Metabolism IL1B extracellular protein P01584 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267486 0.2 SIGNOR-THM Thyroid Hormone Metabolism DIO3 protein P55073 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266952 0.8 SIGNOR-THM Thyroid Hormone Metabolism iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 23349248 t miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). SIGNOR-259913 0.8 SIGNOR-THM Thyroid Hormone Metabolism 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SIGNOR-THM Thyroid Hormone Metabolism L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 8755651 t scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 SIGNOR-266948 0.8 SIGNOR-THM Thyroid Hormone Metabolism IYD protein Q6PHW0 UNIPROT L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267033 0.8 SIGNOR-THM Thyroid Hormone Metabolism TSHB extracellular protein P01222 UNIPROT TSH extracellular complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 t scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. SIGNOR-267047 0.665 SIGNOR-THM Thyroid Hormone Metabolism L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 9606 16098474 t scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. SIGNOR-266955 0.8 SIGNOR-THM Thyroid Hormone Metabolism 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO1 protein P49895 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 t scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). SIGNOR-267280 0.8 SIGNOR-THM Thyroid Hormone Metabolism UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267484 0.2 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269385 0.714 SIGNOR-TI Transcription initiation TFIID factor complex SIGNOR-C343 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 27096372 t miannu Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. SIGNOR-263934 0.521 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269380 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269341 0.714 SIGNOR-TI Transcription initiation TFIIF complex SIGNOR-C394 SIGNOR RNA Polymerase II factor complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 18218714 t lperfetto Transcription processes in eukaryotes begin with the formation of a pre-initiation complex (PIC), composed of RNA polymerase II (Pol II) associated with five general transcription factors: TFIIB, TFIID, TFIIE, TFIIF, and TFIIH SIGNOR-266199 0.722 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269344 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269364 0.714 SIGNOR-TI Transcription initiation TFIIIB complex SIGNOR-C393 SIGNOR RNA Polymerase III factor complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 9308965 t lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. SIGNOR-266181 0.64 SIGNOR-TI Transcription initiation SL1 complex complex SIGNOR-C464 SIGNOR UBTF factor protein P17480 UNIPROT up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269567 0.65 SIGNOR-TI Transcription initiation RNA Polymerase III factor complex SIGNOR-C389 SIGNOR small nuclear RNA smallmolecule CHEBI:74035 ChEBI up-regulates quantity chemical modification 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-266144 0.8 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269372 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269339 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269373 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269348 0.714 SIGNOR-TI Transcription initiation TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269362 0.725 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269359 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269366 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269368 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269374 0.714 SIGNOR-TI Transcription initiation RRN3 protein Q9NYV6 UNIPROT RNA Polymerase I factor complex SIGNOR-C390 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 t lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. SIGNOR-269648 0.77 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269376 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269346 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269378 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269379 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269358 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269345 0.714 SIGNOR-TI Transcription initiation RNA Polymerase I factor complex SIGNOR-C390 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).¬† SIGNOR-266159 0.8 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269371 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269340 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269367 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269357 0.714 SIGNOR-TI Transcription initiation TFIIA complex SIGNOR-C395 SIGNOR RNA Polymerase II factor complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 7724559 t lperfetto The human general transcription factor TFIIA is one of several factors involved in specific transcription by RNA polymerase II SIGNOR-266200 0.645 SIGNOR-TI Transcription initiation WICH complex SIGNOR-C449 SIGNOR RNA Polymerase III factor complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 16603771 t miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. SIGNOR-268829 0.391 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269337 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269343 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269350 0.714 SIGNOR-TI Transcription initiation TFIID factor complex SIGNOR-C343 SIGNOR TFIIA complex SIGNOR-C395 SIGNOR up-regulates activity relocalization 9606 8990153 t lperfetto PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH. SIGNOR-269307 0.596 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269382 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269349 0.714 SIGNOR-TI Transcription initiation WICH complex SIGNOR-C449 SIGNOR RNA Polymerase I factor complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 16514417 t miannu Here, we show by biochemical fractionation of nuclear extracts, protein-protein interaction studies and chromatin immunoprecipitation assays that NM1 is part of a multiprotein complex that contains WICH, a chromatin remodelling complex containing WSTF (Williams syndrome transcription factor) and SNF2h. NM1, WSTF and SNF2h were found to be associated with RNA polymerase I (Pol I) and ribosomal RNA genes (rDNA). RNA interference-mediated knockdown of NM1 and WSTF reduced pre-rRNA synthesis in vivo, and antibodies to WSTF inhibited Pol I transcription on pre-assembled chromatin templates but not on naked DNA. The results indicate that NM1 cooperates with WICH to facilitate transcription on chromatin. SIGNOR-268830 0.435 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269336 0.714 SIGNOR-TI Transcription initiation TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269363 0.725 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269333 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269351 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269352 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269381 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269347 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269369 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269383 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269370 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269365 0.714 SIGNOR-TI Transcription initiation TFIIIC factor complex SIGNOR-C392 SIGNOR RNA Polymerase III factor complex SIGNOR-C389 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 9308965 t lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. SIGNOR-266182 0.443 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269384 0.714 SIGNOR-TI Transcription initiation RNA Polymerase III factor complex SIGNOR-C389 SIGNOR transfer RNA smallmolecule CHEBI:17843 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-266143 0.8 SIGNOR-TI Transcription initiation Core mediator complex complex SIGNOR-C405 SIGNOR RNA Polymerase II factor complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 25693131 t miannu The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation. SIGNOR-266682 0.342 SIGNOR-TI Transcription initiation RNA Polymerase I factor complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 f lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266177 0.7 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269375 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269377 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269338 0.714 SIGNOR-TI Transcription initiation RNA Polymerase II factor complex SIGNOR-C391 SIGNOR precursor messenger RNA smallmolecule CHEBI:139356 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. SIGNOR-266176 0.8 SIGNOR-TI Transcription initiation UBTF factor protein P17480 UNIPROT RNA Polymerase I factor complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269568 0.481 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269342 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269335 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269334 0.714 SIGNOR-TI Transcription initiation TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269386 0.714 SIGNOR-TI Transcription initiation POLR2A protein P24928 UNIPROT RNA Polymerase II factor complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266160 0.863 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.818 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.748 SIGNOR-TLR Toll like receptors TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.887 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 t lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236093 0.48 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 t lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction SIGNOR-178053 0.622 SIGNOR-TLR Toll like receptors NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 SIGNOR-TLR Toll like receptors MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-TLR Toll like receptors IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.883 SIGNOR-TLR Toll like receptors TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 24352680 t lperfetto Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain SIGNOR-216301 0.2 SIGNOR-TLR Toll like receptors MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 8131746 t lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. SIGNOR-244881 0.641 SIGNOR-TLR Toll like receptors MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10347227 t lperfetto However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-236122 0.2 SIGNOR-TLR Toll like receptors TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 17135271 t These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK. SIGNOR-252099 0.2 SIGNOR-TLR Toll like receptors ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-252359 0.784 SIGNOR-TLR Toll like receptors AP1 factor complex SIGNOR-C154 SIGNOR Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 SIGNOR-TLR Toll like receptors MAPK8 protein P45983 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant SIGNOR-183489 0.555 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 t lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. SIGNOR-120355 0.818 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. SIGNOR-209759 0.713 SIGNOR-TLR Toll like receptors TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 9606 BTO:0000007 16371247 f The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6. SIGNOR-252254 0.43 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178363 0.732 SIGNOR-TLR Toll like receptors IRF3 factor protein Q14653 UNIPROT Interferon_Production phenotypesList phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-126962 0.7 SIGNOR-TLR Toll like receptors IRF3 factor protein Q14653 UNIPROT Immune_response phenotypesList phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 SIGNOR-TLR Toll like receptors IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 t lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. SIGNOR-44234 0.911 SIGNOR-TLR Toll like receptors NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.803 SIGNOR-TLR Toll like receptors IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 t lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 SIGNOR-92994 0.911 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178379 0.732 SIGNOR-TLR Toll like receptors MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-232156 0.71 SIGNOR-TLR Toll like receptors NFKBIA protein P25963 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 t lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. SIGNOR-64092 0.803 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. SIGNOR-236145 0.748 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178399 0.818 SIGNOR-TLR Toll like receptors MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 t amattioni Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183). SIGNOR-83736 0.682 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178371 0.732 SIGNOR-TLR Toll like receptors MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51203 0.682 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178375 0.732 SIGNOR-TLR Toll like receptors IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-216341 0.811 SIGNOR-TLR Toll like receptors TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 14530355 t lperfetto Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling SIGNOR-118458 0.812 SIGNOR-TLR Toll like receptors NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR Interferon_Production phenotypesList phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-216322 0.7 SIGNOR-TLR Toll like receptors MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 t gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. SIGNOR-51199 0.682 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178391 0.818 SIGNOR-TLR Toll like receptors IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216385 0.883 SIGNOR-TLR Toll like receptors MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51211 0.706 SIGNOR-TLR Toll like receptors MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-236116 0.728 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000567 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. SIGNOR-55716 0.655 SIGNOR-TLR Toll like receptors SARM1 protein Q6SZW1 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates binding 10090 17667936 t gcesareni SARM utilizes its TIR domain to negatively regulate TRIF SIGNOR-252068 0.552 SIGNOR-TLR Toll like receptors TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 25948473 t lperfetto Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively. SIGNOR-110215 0.616 SIGNOR-TLR Toll like receptors TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 18758450 t lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. SIGNOR-180562 0.2 SIGNOR-TLR Toll like receptors IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.883 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178403 0.818 SIGNOR-TLR Toll like receptors TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 SIGNOR-TLR Toll like receptors TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 9606 BTO:0000801 14519765 t lperfetto Tram binds trif directly and recruits it to tlr4 SIGNOR-118367 0.564 SIGNOR-TLR Toll like receptors MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40353 0.71 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178395 0.818 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000801 20717897 t lperfetto The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation. SIGNOR-167524 0.501 SIGNOR-TLR Toll like receptors MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 t lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. SIGNOR-70607 0.728 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 t lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. SIGNOR-42402 0.48 SIGNOR-TLR Toll like receptors MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf SIGNOR-244892 0.551 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178387 0.732 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. SIGNOR-246643 0.47 SIGNOR-TLR Toll like receptors MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. SIGNOR-40349 0.71 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178383 0.732 SIGNOR-TLR Toll like receptors MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 t lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. SIGNOR-67143 0.844 SIGNOR-TLR Toll like receptors MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 t lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. SIGNOR-236103 0.71 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9480845 f lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway SIGNOR-55710 0.637 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178420 0.818 SIGNOR-TLR Toll like receptors DAMPS extracellular stimulus SIGNOR-ST18 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 25644504 t The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) SIGNOR-252096 0.7 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. SIGNOR-249367 0.501 SIGNOR-TLR Toll like receptors MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 t lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. SIGNOR-40356 0.71 SIGNOR-TLR Toll like receptors MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40423 0.728 SIGNOR-TLR Toll like receptors MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-244904 0.551 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT NfKb-p65/p50 factor complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-217379 0.436 SIGNOR-TLR Toll like receptors IKBKE protein Q14164 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178367 0.732 SIGNOR-TLR Toll like receptors IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-209773 0.883 SIGNOR-TLR Toll like receptors TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways SIGNOR-216298 0.2 SIGNOR-TLR Toll like receptors MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 t lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase SIGNOR-40427 0.728 SIGNOR-TLR Toll like receptors TBK1 protein Q9UHD2 UNIPROT IRF3 factor protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178407 0.818 SIGNOR-TLR Toll like receptors MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 t lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a SIGNOR-217445 0.713 SIGNOR-TLR Toll like receptors MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51207 0.706 SIGNOR-TLR Toll like receptors TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252063 0.616 SIGNOR-TLR Toll like receptors MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 t gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 SIGNOR-59679 0.427 SIGNOR-TLR Toll like receptors PAMPs extracellular stimulus SIGNOR-ST11 SIGNOR TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 SIGNOR-TLR Toll like receptors TLRs receptor proteinfamily SIGNOR-PF20 SIGNOR TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 9606 20404851 t lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways SIGNOR-216307 0.2 SIGNOR-TSC TGFb in cancer TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32748 0.703 SIGNOR-TSC TGFb in cancer TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255962 0.703 SIGNOR-TSC TGFb in cancer CDKN2A protein P42771 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 f Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. SIGNOR-259406 0.7 SIGNOR-TSC TGFb in cancer SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235188 0.701 SIGNOR-TSC TGFb in cancer SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256286 0.586 SIGNOR-TSC TGFb in cancer TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 t miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. SIGNOR-256179 0.2 SIGNOR-TSC TGFb in cancer SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 0.701 SIGNOR-TSC TGFb in cancer SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256287 0.586 SIGNOR-TSC TGFb in cancer SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235178 0.701 SIGNOR-TSC TGFb in cancer SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 t gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-235168 0.691 SIGNOR-TSC TGFb in cancer CDKN2B protein P42772 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 f The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. SIGNOR-259407 0.7 SIGNOR-TSC TGFb in cancer TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246732 0.703 SIGNOR-TSC TGFb in cancer SMAD2/SMAD4 factor complex SIGNOR-C8 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256180 0.528 SIGNOR-TSC TGFb in cancer TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.82 SIGNOR-TSC TGFb in cancer AP1 factor complex SIGNOR-C154 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 SIGNOR-TSC TGFb in cancer SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.628 SIGNOR-TSC TGFb in cancer SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 0.691 SIGNOR-TSC TGFb in cancer TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus SIGNOR-235385 0.806 SIGNOR-TSC TGFb in cancer TGFBR1 receptor protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-236107 0.82 SIGNOR-TSC TGFb in cancer SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR AP1 factor complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 t miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. SIGNOR-256181 0.628 SIGNOR-TSC TGFb in cancer TGFb extracellular proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 receptor protein P37173 UNIPROT up-regulates activity binding 9606 22326956 t miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-256178 0.2 SIGNOR-TSC TGFb in cancer TGFBR1 receptor protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus SIGNOR-235380 0.806 SIGNOR-TSC TGFb in cancer TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 t lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta SIGNOR-246728 0.703 SIGNOR-TSC TGFb in cancer SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 factor complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229557 0.691 SIGNOR-TSC TGFb in cancer TGFBR2 receptor protein P37173 UNIPROT TGFBR1 receptor protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 t lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. SIGNOR-32744 0.703 SIGNOR-VDM Vitamin-D Metabolism CYP27B1 protein O15528 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270559 0.8 SIGNOR-VDM Vitamin-D Metabolism cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270561 0.8 SIGNOR-VDM Vitamin-D Metabolism CYP24A1 protein Q07973 UNIPROT calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270571 0.8 SIGNOR-VDM Vitamin-D Metabolism CYP2R1 protein Q6VVX0 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270569 0.8 SIGNOR-VDM Vitamin-D Metabolism calcitriol smallmolecule CHEBI:17823 ChEBI propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270573 0.8 SIGNOR-VDM Vitamin-D Metabolism vitamin D smallmolecule CHEBI:27300 ChEBI calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270567 0.8 SIGNOR-VDM Vitamin-D Metabolism Food intake extracellular phenotype SIGNOR-PH152 SIGNOR vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity 9606 30080183 f lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. SIGNOR-270565 0.7 SIGNOR-VDM Vitamin-D Metabolism CYP24A1 protein Q07973 UNIPROT propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270574 0.8 SIGNOR-VDM Vitamin-D Metabolism CYP2R1 protein Q6VVX0 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270568 0.8 SIGNOR-VDM Vitamin-D Metabolism calcidiol smallmolecule CHEBI:17933 ChEBI calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity precursor of 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270558 0.8 SIGNOR-VDM Vitamin-D Metabolism calciol smallmolecule CHEBI:28940 ChEBI vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270564 0.8 SIGNOR-VDM Vitamin-D Metabolism UVB radiation stimulus SIGNOR-ST17 SIGNOR calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity chemical modification 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270562 0.7 SIGNOR-VDM Vitamin-D Metabolism GC protein P02774 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity relocalization 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270566 0.8 SIGNOR-VDM Vitamin-D Metabolism calcitriol smallmolecule CHEBI:17823 ChEBI calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270570 0.8 SIGNOR-VEGF VEGF Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.774 SIGNOR-VEGF VEGF Signaling calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 SIGNOR-VEGF VEGF Signaling ITPR1 receptor protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256238 0.8 SIGNOR-VEGF VEGF Signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 t lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 SIGNOR-252712 0.8 SIGNOR-VEGF VEGF Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251628 0.2 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 22264731 t VEGF pathway Gianni Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation SIGNOR-261945 0.471 SIGNOR-VEGF VEGF Signaling 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 12954613 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. SIGNOR-100254 0.8 SIGNOR-VEGF VEGF Signaling NOS3 protein P29474 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24379783 t lperfetto Nitric oxide (NO) is a major mediator of endothelial function and is synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS). SIGNOR-251629 0.8 SIGNOR-VEGF VEGF Signaling VEGFC extracellular protein P49767 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown SIGNOR-55208 0.913 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 16835467 t gcesareni (vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1) SIGNOR-147870 0.657 SIGNOR-VEGF VEGF Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 t lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-244827 0.774 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11278468 t Gianni These results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth. SIGNOR-261916 0.55 SIGNOR-VEGF VEGF Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) SIGNOR-244480 0.73 SIGNOR-VEGF VEGF Signaling SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 t lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. SIGNOR-39237 0.886 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157089 0.2 SIGNOR-VEGF VEGF Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 t lperfetto Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events. SIGNOR-66040 0.2 SIGNOR-VEGF VEGF Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 SIGNOR-VEGF VEGF Signaling VEGFA extracellular protein P15692 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157100 0.816 SIGNOR-VEGF VEGF Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-39163 0.91 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157093 0.2 SIGNOR-VEGF VEGF Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-147327 0.873 SIGNOR-VEGF VEGF Signaling PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28243 0.912 SIGNOR-VEGF VEGF Signaling AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-244322 0.2 SIGNOR-VEGF VEGF Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. SIGNOR-235478 0.873 SIGNOR-VEGF VEGF Signaling CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 24379783 t lperfetto Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-251615 0.751 SIGNOR-VEGF VEGF Signaling BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 t lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-244843 0.774 SIGNOR-VEGF VEGF Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. SIGNOR-243203 0.73 SIGNOR-VEGF VEGF Signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 t lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-252722 0.8 SIGNOR-VEGF VEGF Signaling PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28247 0.912 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157085 0.2 SIGNOR-VEGF VEGF Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.743 SIGNOR-VEGF VEGF Signaling 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 receptor protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 SIGNOR-VEGF VEGF Signaling PXN protein P49023 UNIPROT Cell_migration phenotypesList phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 18650496 f VEGF pathway Gianni Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival. SIGNOR-261944 0.7 SIGNOR-VEGF VEGF Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-134477 0.73 SIGNOR-VEGF VEGF Signaling nitric oxide smallmolecule CHEBI:16480 ChEBI Vascular_Permeability phenotypesList phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 BTO:0001176 24078390 f VEGF pathway Gianni After a period of controversial reports, evidence based on eNOS knockout mice and on eNOS-depleted EC established that microvascular hyperpermeability in response to an inflammatory challenge is regulated mainly by endothelial cells through eNOS-derived NO SIGNOR-261947 0.7 SIGNOR-VEGF VEGF Signaling PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257732 0.912 SIGNOR-VEGF VEGF Signaling PI3K complex SIGNOR-C156 SIGNOR PIP3 receptor smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 t lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. SIGNOR-252713 0.8 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157081 0.2 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. SIGNOR-261948 0.67 SIGNOR-VEGF VEGF Signaling VEGFD extracellular protein O43915 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates binding 9606 9435229 t gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. SIGNOR-55163 0.2 SIGNOR-VEGF VEGF Signaling PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 t lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. SIGNOR-244396 0.73 SIGNOR-VEGF VEGF Signaling BAD protein Q92934 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 f irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. SIGNOR-256260 0.7 SIGNOR-VEGF VEGF Signaling PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176606 0.8 SIGNOR-VEGF VEGF Signaling 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i. SIGNOR-179291 0.8 SIGNOR-VEGF VEGF Signaling PIP3 receptor smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 t lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. SIGNOR-175253 0.8 SIGNOR-VEGF VEGF Signaling HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 t lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. SIGNOR-160043 0.873 SIGNOR-VEGF VEGF Signaling PLCG1 protein P19174 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176609 0.8 SIGNOR-VEGF VEGF Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-236792 0.91 SIGNOR-VEGF VEGF Signaling MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244776 0.743 SIGNOR-VEGF VEGF Signaling KDR receptor protein P35968 UNIPROT KDR receptor protein P35968 UNIPROT up-regulates phosphorylation Tyr951 RFRQGKDyVGAIPVD 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157097 0.2 SIGNOR-VEGF VEGF Signaling ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 f In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. SIGNOR-254354 0.7 SIGNOR-VEGF VEGF Signaling GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 t GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. SIGNOR-235773 0.91 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates activity chemical modification 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265917 0.8 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265926 0.484 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT BGLAP extracellular protein P02818 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265922 0.673 SIGNOR-VKC Vitamin-K cycle Food intake extracellular phenotype SIGNOR-PH152 SIGNOR vitamin K extracellular smallmolecule CHEBI:28384 ChEBI up-regulates quantity 31226734 f lperfetto Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system  SIGNOR-265899 0.7 SIGNOR-VKC Vitamin-K cycle vitamin K epoxide smallmolecule CHEBI:28371 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265913 0.8 SIGNOR-VKC Vitamin-K cycle VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265901 0.8 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT F2 extracellular protein P00734 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265918 0.653 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT F10 extracellular protein P00742 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265921 0.595 SIGNOR-VKC Vitamin-K cycle CALU protein O43852 UNIPROT GGCX protein P38435 UNIPROT down-regulates activity binding 10116 BTO:0000759 15075329 t lperfetto Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity. SIGNOR-265910 0.417 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265919 0.674 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT PROS1 extracellular protein P07225 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265924 0.599 SIGNOR-VKC Vitamin-K cycle VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265905 0.8 SIGNOR-VKC Vitamin-K cycle vitamin K extracellular smallmolecule CHEBI:28384 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265915 0.8 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265920 0.669 SIGNOR-VKC Vitamin-K cycle warfarin chemical CHEBI:10033 ChEBI VKORC1 protein Q9BQB6 UNIPROT down-regulates activity chemical inhibition 9606 27941861 t lperfetto Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. SIGNOR-265911 0.8 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT GAS6 extracellular protein Q14393 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265923 0.503 SIGNOR-VKC Vitamin-K cycle GGCX protein P38435 UNIPROT PROC protein P04070 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265925 0.549 SIGNOR-VKC Vitamin-K cycle Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265909 0.8 SIGNOR-WC Wnt in cancer RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259998 0.516 SIGNOR-WC Wnt in cancer Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. SIGNOR-255891 0.2 SIGNOR-WC Wnt in cancer LPR5/6 receptor complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. miannu These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin. SIGNOR-256177 0.698 SIGNOR-WC Wnt in cancer LEF1 factor protein Q9UJU2 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.622 SIGNOR-WC Wnt in cancer DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227911 0.7 SIGNOR-WC Wnt in cancer MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 f andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation SIGNOR-255414 0.7 SIGNOR-WC Wnt in cancer GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 SIGNOR-WC Wnt in cancer CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 f Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. SIGNOR-255654 0.7 SIGNOR-WC Wnt in cancer CTNNB1 protein P35222 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 f apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion SIGNOR-255695 0.7 SIGNOR-WC Wnt in cancer CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome SIGNOR-165022 0.782 SIGNOR-WC Wnt in cancer Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 receptor complex SIGNOR-C219 SIGNOR up-regulates activity binding 9606 23209147 t miannu FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles. SIGNOR-256174 0.802 SIGNOR-WC Wnt in cancer GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 SIGNOR-WC Wnt in cancer LEF1 factor protein Q9UJU2 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 SIGNOR-WC Wnt in cancer Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 t miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 0.834 SIGNOR-WC Wnt in cancer GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 SIGNOR-WC Wnt in cancer CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 SIGNOR-WNT WNT Signaling CTNNB1 protein P35222 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.737 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 t gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. SIGNOR-148671 0.783 SIGNOR-WNT WNT Signaling PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144478 0.454 SIGNOR-WNT WNT Signaling WNT7A extracellular protein O00755 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131900 0.587 SIGNOR-WNT WNT Signaling Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 t miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 0.834 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131826 0.69 SIGNOR-WNT WNT Signaling LEF1 factor protein Q9UJU2 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 SIGNOR-WNT WNT Signaling Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. SIGNOR-253125 0.2 SIGNOR-WNT WNT Signaling DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 t lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-227917 0.7 SIGNOR-WNT WNT Signaling LRP6 receptor protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. lperfetto These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. SIGNOR-227942 0.723 SIGNOR-WNT WNT Signaling LRP5 receptor protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 t lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes SIGNOR-227930 0.672 SIGNOR-WNT WNT Signaling JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-WNT WNT Signaling ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 15068801 t gcesareni Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter. SIGNOR-123717 0.302 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 SIGNOR-WNT WNT Signaling DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 0.815 SIGNOR-WNT WNT Signaling WNT11 extracellular protein O96014 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131637 0.568 SIGNOR-WNT WNT Signaling CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 SIGNOR-WNT WNT Signaling DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185274 0.561 SIGNOR-WNT WNT Signaling LEF1 factor protein Q9UJU2 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229767 0.7 SIGNOR-WNT WNT Signaling DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227914 0.7 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.891 SIGNOR-WNT WNT Signaling MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-WNT WNT Signaling MYC factor protein P01106 UNIPROT DKK1 extracellular protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17485441 f gcesareni C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245355 0.402 SIGNOR-WNT WNT Signaling CREB1 factor protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 8355 10775268 f lperfetto Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter SIGNOR-76984 0.471 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 t lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 0.891 SIGNOR-WNT WNT Signaling CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome SIGNOR-165022 0.782 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 0.891 SIGNOR-WNT WNT Signaling DKK1 extracellular protein O94907 UNIPROT LRP6 receptor protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6. SIGNOR-109247 0.901 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 0.891 SIGNOR-WNT WNT Signaling SFRP1 extracellular protein Q8N474 UNIPROT WNT1 extracellular protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-67806 0.776 SIGNOR-WNT WNT Signaling PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144482 0.454 SIGNOR-WNT WNT Signaling MYC factor protein P01106 UNIPROT SFRP1 extracellular protein Q8N474 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004896; BTO:0004300 17485441 f gcesareni c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245360 0.369 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131829 0.783 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169657 0.69 SIGNOR-WNT WNT Signaling Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253124 0.2 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 SIGNOR-WNT WNT Signaling RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.643 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169660 0.783 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227885 0.891 SIGNOR-WNT WNT Signaling WNT5A extracellular protein P41221 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131841 0.749 SIGNOR-WNT WNT Signaling WNT1 extracellular protein P04628 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169648 0.823 SIGNOR-WNT WNT Signaling WNT1 extracellular protein P04628 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-253126 0.757 SIGNOR-WNT WNT Signaling DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199381 0.42 SIGNOR-WNT WNT Signaling CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 t lperfetto Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-227866 0.891 SIGNOR-WNT WNT Signaling WNT7A extracellular protein O00755 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-253130 0.759 SIGNOR-WNT WNT Signaling WNT7A extracellular protein O00755 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131903 0.634 SIGNOR-WNT WNT Signaling CREB1 factor protein P16220 UNIPROT Survival phenotypesList phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 SIGNOR-WNT WNT Signaling DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199384 0.561 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227889 0.891 SIGNOR-WNT WNT Signaling JUN factor protein P05412 UNIPROT Cell_migration phenotypesList phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 23151663 f amattioni Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor. SIGNOR-229760 0.7 SIGNOR-WNT WNT Signaling 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 t milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 0.8 SIGNOR-WNT WNT Signaling PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. SIGNOR-250047 0.495 SIGNOR-WNT WNT Signaling WNT5A extracellular protein P41221 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253129 0.828 SIGNOR-WNT WNT Signaling LEF1 factor protein Q9UJU2 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.622 SIGNOR-WNT WNT Signaling WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169645 0.78 SIGNOR-WNT WNT Signaling WNT11 extracellular protein O96014 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253127 0.702 SIGNOR-WNT WNT Signaling WNT3A extracellular protein P56704 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling. SIGNOR-253128 0.802 SIGNOR-WNT WNT Signaling MAPK8 protein P45983 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236018 0.579 SIGNOR-WNT WNT Signaling GNAS protein P63092 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-227988 0.389 SIGNOR-WNT WNT Signaling MAPK8 protein P45983 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169007 0.395 SIGNOR-WNT WNT Signaling GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 0.891 SIGNOR-WNT WNT Signaling DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185271 0.724 SIGNOR-WNT WNT Signaling GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.611 SIGNOR-WNT WNT Signaling Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 SIGNOR-WNT WNT Signaling WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131574 0.78 SIGNOR-WNT WNT Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-WNT WNT Signaling MAPK8 protein P45983 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236384 0.579 SIGNOR-WNT WNT Signaling CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 SIGNOR-WNT WNT Signaling ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 t milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 0.8 SIGNOR-WNT WNT Signaling MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199384 0.561 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185271 0.724 SIGNOR-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 FLT3 receptor protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 BTO:0001516 23246379 f miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-260083 0.537 SIGNOR-WNT/FLT3 WNT/FLT3 FLT3 receptor protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 f These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261521 0.298 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-WNT/FLT3 WNT/FLT3 Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 11955436 t gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-116520 0.857 SIGNOR-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.72 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236384 0.579 SIGNOR-WNT/FLT3 WNT/FLT3 TCF4 factor protein P15884 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18852287 t Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. SIGNOR-253324 0.385 SIGNOR-WNT/FLT3 WNT/FLT3 GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.611 SIGNOR-WNT/FLT3 WNT/FLT3 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. SIGNOR-250047 0.495 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-WNT/FLT3 WNT/FLT3 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 t gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-199504 0.857 SIGNOR-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-217586 0.72 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT MYC factor protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 t lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-236018 0.579 SIGNOR-WNT/FLT3 WNT/FLT3 LEF1 factor protein Q9UJU2 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-245351 0.622 SIGNOR-WNT/FLT3 WNT/FLT3 CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 SIGNOR-WNT/FLT3 WNT/FLT3 SFRP1 extracellular protein Q8N474 UNIPROT Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR down-regulates binding 9606 BTO:0000782 10347172 t gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. SIGNOR-262527 0.786 SIGNOR-WNT/FLT3 WNT/FLT3 MAPK8 protein P45983 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169007 0.395 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding 9606 SIGNOR-C110 20837657 t gcesareni In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-167957 0.605 SIGNOR-WNT/FLT3 WNT/FLT3 Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253124 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 ADCY1 protein Q08828 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 27065076 f Gianni Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA) SIGNOR-262528 0.488 SIGNOR-WNT/FLT3 WNT/FLT3 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144482 0.454 SIGNOR-WNT/FLT3 WNT/FLT3 CTNNB1 protein P35222 UNIPROT TCF4 factor protein P15884 UNIPROT up-regulates activity binding 9606 BTO:0000007 11713476 t amattioni beta-catenin interacts with the TCF/Lef family transcription factors. SIGNOR-178042 0.674 SIGNOR-WNT/FLT3 WNT/FLT3 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.643 SIGNOR-WNT/FLT3 WNT/FLT3 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185274 0.561 SIGNOR-WNT/FLT3 WNT/FLT3 DKK1 extracellular protein O94907 UNIPROT LRP6 receptor protein O75581 UNIPROT down-regulates binding 9606 11448771 t gcesareni We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6. SIGNOR-109247 0.901 SIGNOR-WNT/FLT3 WNT/FLT3 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262522 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199381 0.42 SIGNOR-WNT/FLT3 WNT/FLT3 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-256063 0.7 SIGNOR-WNT/FLT3 WNT/FLT3 MYC factor protein P01106 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 f gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. SIGNOR-56572 0.7 SIGNOR-WNT/FLT3 WNT/FLT3 FOXO1 factor protein Q12778 UNIPROT TCF4 factor protein P15884 UNIPROT down-regulates activity binding 9606 BTO:0000797 18250171 t Gianni Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. SIGNOR-262529 0.272 SIGNOR-WNT/FLT3 WNT/FLT3 LRP6 receptor protein O75581 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 t Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. SIGNOR-262526 0.697 SIGNOR-WNT/FLT3 WNT/FLT3 CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 SIGNOR-WNT/FLT3 WNT/FLT3 CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 SIGNOR-WNT/FLT3 WNT/FLT3 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144478 0.454 SIGNOR-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 factor protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. SIGNOR-252346 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 0.815 SIGNOR-WNT/FLT3 WNT/FLT3 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252703 0.785 SIGNOR-WNT/FLT3 WNT/FLT3 MYC factor protein P01106 UNIPROT DKK1 extracellular protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17485441 f gcesareni C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245355 0.402 SIGNOR-WNT/FLT3 WNT/FLT3 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245428 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome SIGNOR-165022 0.782 SIGNOR-WNT/FLT3 WNT/FLT3 CTNNB1 protein P35222 UNIPROT MYC factor protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 f gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-19153 0.737 SIGNOR-WNT/FLT3 WNT/FLT3 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 15068801 t gcesareni Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter. SIGNOR-123717 0.302 SIGNOR-WNT/FLT3 WNT/FLT3 JUN factor protein P05412 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. SIGNOR-233467 0.7 SIGNOR-WNT/FLT3 WNT/FLT3 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 25010901 t gcesareni Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase SIGNOR-196740 0.804 SIGNOR-WNT/FLT3 WNT/FLT3 Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. SIGNOR-253125 0.2 SIGNOR-WNT/FLT3 WNT/FLT3 MYC factor protein P01106 UNIPROT SFRP1 extracellular protein Q8N474 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004896; BTO:0004300 17485441 f gcesareni c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity SIGNOR-245360 0.369 SIGNOR-WNT/FLT3 WNT/FLT3 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252715 0.785 SIGNOR-WNT/FLT3 WNT/FLT3 Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 t miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-256173 0.834 SIGNOR-WNT/FLT3 WNT/FLT3 LEF1 factor protein Q9UJU2 UNIPROT Proliferation phenotypesList phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144478 0.454 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185274 0.561 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT5A extracellular protein P41221 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131841 0.749 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227914 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. SIGNOR-199378 0.914 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227901 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT1 extracellular protein P04628 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169648 0.823 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT11 extracellular protein O96014 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131637 0.568 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CREB1 factor protein P16220 UNIPROT PAX3 factor protein P23760 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176539 0.323 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 0.815 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CREB1 factor protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 8355 10775268 f lperfetto Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter SIGNOR-76984 0.471 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CREB1 factor protein P16220 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176536 0.476 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 15068801 t gcesareni Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter. SIGNOR-123717 0.302 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 t lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 t gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. SIGNOR-148671 0.783 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT1 extracellular protein P04628 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-253126 0.757 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199381 0.42 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227870 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CTNNB1 protein P35222 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 18316399 t gcesareni We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity. SIGNOR-161113 0.423 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CREB1 factor protein P16220 UNIPROT MYF5 factor protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 f gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. SIGNOR-176533 0.294 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis LRP5 receptor protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 t lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes SIGNOR-227930 0.672 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT1 extracellular protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription SIGNOR-85760 0.736 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis LRP6 receptor protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. lperfetto These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. SIGNOR-227942 0.723 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis MYF5 factor protein P13349 UNIPROT Skeletal_muscle_differentiation phenotypesList phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. SIGNOR-37409 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227878 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 t gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 SIGNOR-134219 0.914 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT7A extracellular protein O00755 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-253130 0.759 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144482 0.454 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis JUN factor protein P05412 UNIPROT Brown_adipogenesis phenotypesList phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198834 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 t lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. SIGNOR-227917 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169657 0.69 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT7A extracellular protein O00755 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131900 0.587 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131829 0.783 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-253124 0.2 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. SIGNOR-253125 0.2 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 t lperfetto Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. SIGNOR-227866 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have SIGNOR-169660 0.783 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.643 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 0.8 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227885 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis ROCK1 protein Q13464 UNIPROT Brown_adipogenesis phenotypesList phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198840 0.7 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131826 0.69 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR LRP6 receptor protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 10090 BTO:0002572 16341017 t gcesareni Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. SIGNOR-228014 0.723 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PITX2 factor protein Q99697 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 20978076 f gcesareni We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer. SIGNOR-169107 0.455 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PAX3 factor protein P23760 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 20006729 t gcesareni Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1. SIGNOR-162100 0.441 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-156958 0.611 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 t gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. SIGNOR-176560 0.559 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis CTNNB1 protein P35222 UNIPROT LEF1 factor protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 t gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. SIGNOR-169632 0.914 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131574 0.78 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199384 0.561 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT7A extracellular protein O00755 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131903 0.634 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis Wnt extracellular proteinfamily SIGNOR-PF40 SIGNOR LRP6 receptor protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-152808 0.643 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GNAS protein P63092 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-227988 0.389 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. SIGNOR-235766 0.905 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis MAPK8 protein P45983 UNIPROT JUN factor protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.905 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. SIGNOR-227881 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT3A extracellular protein P56704 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling. SIGNOR-253128 0.802 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PAX3 factor protein P23760 UNIPROT MYOD1 factor protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181621 0.502 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 23151663 t gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. SIGNOR-199542 0.804 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis LEF1 factor protein Q9UJU2 UNIPROT MYF5 factor protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 16936075 f The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1. gcesareni Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer. SIGNOR-149170 0.256 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT11 extracellular protein O96014 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253127 0.702 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT1 extracellular protein P04628 UNIPROT LRP5 receptor protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. SIGNOR-169645 0.78 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis WNT5A extracellular protein P41221 UNIPROT Frizzled receptor proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253129 0.828 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 16199882 t gcesareni Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro. SIGNOR-140902 0.454 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 t milica The cAMP signaling cascade can activate protein kinase a (PKA) SIGNOR-198492 0.8 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates activity phosphorylation 10116 BTO:0001593 18981475 t gcesareni These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit. SIGNOR-181979 0.2 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185271 0.724 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PAX3 factor protein P23760 UNIPROT PITX2 factor protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21143873 f gcesareni Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis. SIGNOR-170343 0.282 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis LEF1 factor protein Q9UJU2 UNIPROT PITX2 factor protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 19850024 f gcesareni These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway SIGNOR-188730 0.707 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT CREB1 factor protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 t gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 0.559 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 t miannu PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. SIGNOR-250047 0.495 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis PAX3 factor protein P23760 UNIPROT MYF5 factor protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 23384562 f gcesareni Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer. SIGNOR-200862 0.494 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis MAPK8 protein P45983 UNIPROT LRP6 receptor protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169007 0.395 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227889 0.891 SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 t milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. SIGNOR-198486 0.8