sig_id path_name path_description path_curator SIGNOR-AAAM Aspartate and asparagine metabolism Marta Iannuccelli SIGNOR-AC Adipogenesis The transition from precursor stem cells into mature adipocytes is a very complex and highly controlled process. Several molecules, pathways and signals are required to accomplish this orchestrated programme. Multiple signals can influence whether stem cells form adipocytes, including extracellular factors such as the bone morphogenetic proteins (BMP 2/4/7), insulin (INS) and hormones (Glucocorticoids). All these factors activate the Peroxisome proliferator-activated receptor gamma (PPARG), that promotes the maturation of adipocytes. Filomena Spada SIGNOR-AD Alzheimer Alzheimer's disease (AD) is one of the major causes of dementia, AD 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. The senile plaques are generated by a deposition in the human brain of fibrils of the beta-amyloid peptide (Abeta), 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).Two main protein kinases have been shown to be involved in anomalous tau phosphorylations: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3beta. Several different studies have provided evidence implicating oxidative stress, calcium balance and mitochondrial apoptotic pathways a as major pathogenic mechanism in AD. Livia Perfetto SIGNOR-AG Axon guidance Marta Iannuccelli SIGNOR-AML Acute Myeloid Leukemia Livia Perfetto SIGNOR-AML1-ETO AML1-ETO in AML The t(8;21) (q21;q22) translocation is among the commonest rearrangements in AML, causing enhanced marrow granulopoiesis with inhibition of erythropoiesis. This translocation causes the formation of the fusion oncoprotein AML1 (chr.21)-ETO (chr.8) joining the transcription factor RUNX1/AML1 fused to ETO. The N-terminal of AML1 interact with CBFb and with RUNX1 DNA binding sites, while ETO recruits a nuclear corepressor complex resulting in the dominant repression of AML1-regulated target genes involved in granulocytic differentiation (i.e. Myeloperoxidase, CDKN2A/p14ARF). CD45/PTPRC, a protein tyrosine phosphatase that acts as a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling is also repressed. AML1/ETO directly interferes with recruitment of essential cofactors by a number of crucial hematopoietic transcription factors such as C/EBPα and PU.1/SPI1. AML1-ETO can also activate genes involved in stem cell self-renewal: Jagged and HES1 (Notch pathway) or Plakoglobin, which binds TCF/LEF and activates the Wnt target genes C-MYC and CYCLIN D1. PMID: 17125917 irozzo SIGNOR-AML-ASXL1 ASXL1 in AML Additional sex combs-like 1 (ASXL1) is a member of the ASXL family and is involved in epigenetic regulation. ASXL mutations in AML are predominantly frameshift and nonsense mutations generating C-terminally truncated proteins, and are associated with a poor prognosis. The N-terminal ASXH domain mediates interaction with a nuclear ubiquitin carboxy-terminal hydrolase, BAP1. BAP1 is an essential component of the “polycomb repressive deubiquinase complex” (PR-DUB), which leads to gene repression. How ASXL1 mutations, mostly heterozygous somatic mutation, induce myeloid transformation is not fully understood. ASXL1 gene may act as a aploinsufficient or dominant negative tumor suppressor, since loss of ASXL1 function (in promoting H3K27me3) contributes to myeloid transformation and ASXL1 is specifically required for the increased expression of p15(INK4B), in response to oncogenic signaling. On the other hand, cancer-associated ASXL1 mutations aberrantly enhance BAP1. This hyperactive mutant ASXL1/BAP1 complex induces upregulation of posterior HOXA genes and IRF8, thus impairing multilineage differentiation of haematopoietic progenitors. (PMID: 30013160; PMID: 26470845) irozzo SIGNOR-AML-BCRABL BCR-ABL in AML The t(9;22)(q34;q11) reciprocal translocation (Philadelphia chromosome, Ph) is a molecular hallmark of chronic myeloid leukemia (CML). This translocation produces a protein that results from the fusion of BCR (chr. 22) to ABL1 (chr.9). The resulting chimeric proteins have different molecular weights: p190, associated to B-cell acute lymphoblastic leukemia (ALL), p210 (CML) or p230. The BCR-Abl protein is a constitutively activated tyrosine kinase, that triggers the RAS and Jun-kinase signaling playing a major role in transformation and proliferation. Inhibition of apoptosis is thought to result from the activation of the PI-3 kinase/AKT and RAS pathways, with induction of c-myc and BCL-2. BCR/ABL affects the JAK/ STAT signaling, which is constitutively active in BCR/ABL-positive cell lines and in primary cells from CML patients, probably contributing to the induction of cytokine independence. irozzo SIGNOR-AML-DNMT3A DNMT3A in AML In de novo AML, without cytogenetic aberrations, somatic missense mutations of the DNA methyltransferase 3A (DNMT3A) have been frequently (22%) reported. Mammalian DNA methyltransferases (DNMTs) catalyze the transfer of a methyl group onto the 5′-position of cytosine at CpG dinucleotides. DNA methylation regulates the expression of oncogenes and tumor-suppressor genes. DNMT3A forms homo- and heterotetrameric complexes, therefore, mutations in DNMT3A can directly alter DNMT3A function or change the enzyme interaction with partner proteins. In fact, some DNMT3A mutants show enhanced activity, while others show attenuated ability, to methylate target genes.Loss of function of DNMT3A (the best characterized is the mutation R882H) may cause focal promoter hypomethylation, associated to transcriptional reactivation of the leukemogenic HOX cofactor MEIS1 and homeobox genes. On the other end, a subset of AML mutations of DNMT3 display enhanced ability to perform an aberrant, non-CpG methylation, associated with maintaining pluripotency. PMID:26434589; PMID:30705090 irozzo SIGNOR-AML-FLT3 FLT3 in AML FLT3 is a transmembrane class III tyrosine kinase receptor that is activated by the extracellular ligand (FLT3LG)It is expressed by CD34+ hematopoietic stem or progenitor cells and has an important role in the early stages of both the myeloid and the lymphoid lineage development. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene (chr.13q12) occur in approximately 40% of all AML cases. The internal tandem duplications (ITD) represent approximately 30% of all AML cases and can occur in the juxtamembrane domain (JMD) region or in the FLT3 kinase domain TKD1. The mutated receptor is defective in auto-inhibitory control and constitutively activates the RAS, STAT5 and PI3K/AKT pathways. C/EBP (CCAAT/enhancer-binding protein) and PU.1, transcription factors, both implicated in normal myeloid differentiation, are repressed. FoxO3a-mediated apoptosis is prevented. PMID: 25992210 irozzo SIGNOR-AML-FusionProteins Onco-fusion proteins in AML Marta Iannuccelli SIGNOR-AML-IDH_TET IDH-TET in AML Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate(α-KG), which is required for activity of the Methylcytosine Dioxygenase (TET, Ten-Eleven-translocation) enzyme. A group of Acute Myeloid Leukemia (AML) patients (>15%), with normal cytogenetics, harbor missense mutations in either of the two isocitrate dehydrogenase genes, IDH1 or IDH2. The mutated enzymes acquire a neomorphic activity and produce the onco-metabolite 2-hydroxyglutarate (2HG). As a consequence, the TET2 DNA dioxygenase is catalitically inactivated and cannot modulate DNA de-methylation and expression of a number of genes. Loss of function mutations in TET2 are frequently detected in hematopoietic malignancies, in particular AML (~15 – 20%). Some AML-associated TET2 mutations disrupt its binding to the Wilms Tumor transcription factor (WT1). WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of its target genes.Mutations in IDH, TET and WT1 are mutually exclusive since they function along the same pathway. WT1 is overexpressed in a number of of AML patients and its increased levels are associated with resistance to therapy, a higher incidence of relapse, and poor overall survival. Increased glucose levels impede AMPK-mediated phosphorylation of TET2 at serine 99, thus destabilizating TET2. This links diabetes to cancer, metformin and antidiabetic drugs to cancer prevention.PMID: 27252512, 21723201, 19657110, 30022161 miannu SIGNOR-AML-KIT KIT in AML The Class III tyrosine kinase, Stem Cell factor receptor/c-Kit, plays a critical role in hematopoiesis. The Ras/Erk, JAK/STAT and the PI3-kinase/AKT pathways are the key signaling pathways involved in the regulation of cell proliferation, survival, and differentiation induced by c-Kit. KIT activation/gain of function mutations occur in 60-80% of Acute Myeloid Leukemia (AML) patients and in 12.8-46.1% of adults with Core Binding factor (CBF) leukemia. AML chromosomal abnormalities form different subgroups. The AML with fused transcripts such as RUNX1-RUNX1T1 t(8;21)(q22;q22) or CBFbeta-MYH11 inv(16)(p13;q22) form the group Core Binding Factor-AML (CBF-AML). Numerous studies suggest that c-kit mutations could have effects on the relapse and white blood cell increase in CBF-AML adults, expecially in patients with t(8,21). The gain-of-function mutations in the oncogene KIT can transform by different mechanisms, such as: Impair apoptosis (e.g.,by inhibitory phosphorylation of BAD) or induce growth and survival in a ligand independent/altered substrate specificity way. Moreover, a lowered degree of cell surface expression of receptor onco-mutants has been described. The PTPN11 gene encodes the human SHP2 non-receptor tyrosine phosphatase (chr. 12q24), which positively participates in signal events downstream of growth factors receptors and plays a key role in the proliferation and survival of hematopoietic cells. PTPN11 mutations and mutations in FLT3/ITD, KIT, KRAS or CEBPA seem to be mutually exclusive. PMID: 19265199, 27613372, 17972951 irozzo SIGNOR-AML_miRNA miRNA in AML miannu SIGNOR-AML-MLL MLL fusion protein in AML irozzo SIGNOR-AML-NP1 NPM1 in AML Nucleophosmin (NPM1) is the most frequently mutated gene in Acute Myeloid Leukemia (AML). The protein shows a wide tissue distribution, shuttls between nucleus and cytoplasm, but is mainly localized at nucleoli. NPM1 contains a N-terminal nuclear export signal (NES), a bipartite nuclear localization signal (NLS) and a C-terminal nucleolar localization signal (NoLS). NPM1 mutations in AML are always heterozygous and mutually exclusive with AML carrying recurrent genetic abnormalities. In all instances, the nucleolar localization signal is compromised and a new NES appears. In AML with mutated NPM1, the variant nucleophosmin protein is stably delocalized in the cytoplasm and therefore referred to as NPM1c+ (for cytoplasmic positive). The NPM1c+ protein can bind the wild-type counterpart (through the N-terminal portion) and dominantly delocalize the majority of NPM1 in the cytoplasm. NPM1c+ delocalize in the cytoplasm also its physical interactors, the tumor suppressors p14Arf and Fwb7gamma, causing their degradation, which cause decreased levels of p53 and increased c-Myc half life. Moreover NPM1c+ leads to polyubiquitination and degradation of the tumor suppressor PTEN. PMID: 23436734, 18625840 miannu SIGNOR-AML_TF HaematopoiesisTranscriptionalControl miannu SIGNOR-AML_TRIPLETS AML_TRIPLETS Marta Iannuccelli SIGNOR-AMPK AMPK Signaling Maintaining a balanced level of ATP (the immediate source of cellular energy) is essential for the proper functioning of all living cells. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis: AMP-activated protein kinase (AMPK) is activated in response to a fall in ATP (concomitant with a rise in ADP and AMP) level, resulting in the activation of catabolic processes and the inhibition of anabolic processes. Livia Perfetto SIGNOR-Autophagy Autophagy Autophagy is an homeostatic catabolic process by which cells digest their own components in response to internal or external cues, such as nutrient deprivation or infection. The autophagic process involves the formation of a complex machinery coordinated by the action of specific proteic components. SIGNOR-B-cell B-cell activation SIGNOR-CAC Citric acid cycle The citric acid cycle (CAC), also known as the TCA cycle (tricarboxylic acid cycle) or the Krebs cycle, is the primary metabolic pathway by which all aerobic organisms generate energy and is the final common oxidative pathway for carbohydrates, fats and amino acids. The CAC cycle begins with an enzymatic aldol addition reaction of acetyl CoA to oxaloacetate, forming citrate; citrate is then isomerized by a dehydration-hydration sequence to yield isocitrate. Further enzymatic oxidation and decarboxylation gives 2-ketoglutarate that after another enzymatic decarboxylation and oxidation is transformed into succinyl-CoA. The hydrolysis of this metabolite to succinate is coupled to the phosphorylation of ADP or GDP to ATP or GTP. Enzymatic desaturation by flavin adenine dinucleotide (FAD)-dependent succinate dehydrogenase forms fumarate. A stereospecific hydration catalyzed by fumarase transforms fumarate to L-malate.The last step of NAD-coupled oxidation of L-malate to oxaloacetate is catalyzed by malate dehydrogenase and closes the cycle. Marta Iannuccelli SIGNOR-CB Carnitine biosynthesis Marta Iannuccelli SIGNOR-CC Circadian clock Marta Iannuccelli SIGNOR-CCN COVID-19 Causal Network Marta Iannuccelli SIGNOR-CM Catecholamine metabolism Catecholamines (Dopamine, Norepinephrine and Epinephrine) are monoamine neurotransmitters produced by the adrenal gland. Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. Livia Perfetto SIGNOR-CRC Colorectal Carcinoma Colorectal Carcinoma (CRC) is an important contributor to cancer mortality and morbidity. Tow types of CRC can be distinguished: those characterized by microsatellite instability and those that are microsatellite stable but chromosomally unstable. Over the past decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of CRC. A relatively limited number of oncogenes and tumor-suppressor genes—most prominently the APC, KRAS, and p53 genes—are mutated in a sizeable fraction of CRCs. The mutations act to dysregulate conserved signaling pathways (MAPK, PI3K, WNT and p53 pathways) that exert effects on critical cell phenotypes, including proliferation and survival Livia Perfetto SIGNOR-CS Complement Signaling The complement system is an essential part of innate immunity. Three distinct activation pathways belong to the complement system: the classical, lectin, and alternative pathways. They all converge to the cleavage of C3 by C3 convertases. The downstream phases are common to the three pathways: opsonization, anaphylatoxin-mediated inflammation, and formation of terminal membrane attack complex. Classical and Lectin Pathways are shown. In the classical pathway, the cascade is initiated by the interaction between C1q and immunocomplexes, this lead to the activation of C1 that cleaves C4 to C4a and C4b, and C2 to C2a and C2b. In the lectin pathway, MBL and other ficolins are activated by pathogen molecules and up-regulate proteases MASP-1, MASP-2 that cleave intact C4 and C2. The C4b fragment combines with the lipid bilayer of the target cell and C2a to form the C3 convertase C2a4b. Livia Perfetto SIGNOR-DD DNA repair in cancer Marta Iannuccelli SIGNOR-DR Death Receptor Signaling The Death receptor (DR) signaling promotes apoptosis but, depending on the cellular context, it can also promote either prosurviaval and proinflammatory signaling pathways. There are six Tumor necrosis factor receptor (TNFR) family DR identified in human to date: Fas/CD-95, TNFR1, DR3, DR4, DR5, and DR6. These DR are activated by their respective ligands that also form a family of related molecules. The DRs initiate signaling by recruiting one of two platform adaptor molecules: FADD, that generally mediates apoptosis and/or TRADD, that engages both apoptotic and non-apoptotic signaling pathways. These adaptors in turn recruit distinct signaling complexes that mediates the downstream signaling events. This representation is focused on the signaling pathways downstream of DRs that directly promotes apoptosis, and describes pathways initiated by TNFR1 as the prototype of TRADD-mediated DR signaling (TNFR1, DR3, DR6) and Fas-activated pathways as the prototype of FADD-mediated DR signaling (FAS/CD-95, DR4, DR5). Anna Mattioni SIGNOR-DS Dopaminergic Synapse Marta Iannuccelli SIGNOR-EGF EGFR Signaling The epidermal growth factor receptor (EGFR) signaling pathway regulates growth, survival, proliferation, and differentiation. The binding of extracellular ligands (EGF) induces homo and heterodimerization, transphosphorylation and activation of four ErbB family receptors: EGFR (ErbB1), ErbB2, ErbB3, and ErbB4. These events trigger a cascade of activation of downstream pathways that include, principally, the MAPK, Akt and JNK pathways, culminating in DNA synthesis and cell proliferation. Theodora Pavlidou SIGNOR-EI EBV infection Silvia Contino SIGNOR-ES ErbB receptors in cancer miannu SIGNOR-FapINS FAP: Insulin-mediated adipogenesis Insulin pro-adipogenic effects are mainly mediated through the PI3K/AKT pathway, which is responsible for the phosphorylation and subsequent nuclear exclusion of anti-adipogenic transcription factors, such as the forkhead proteins FOXO1 and FOXA2. Another target of AKT-mediated modulation is GATA2 that exerts its anti-adipogenic activity through direct inhibition of several adipogenic factors, including PPARγ. Andrea Cerquone Perpetuini SIGNOR-FattyAcidSynthesis Fatty Acid Synthesis Luisa SIGNOR-Fibrosis Fibrosis Transforming growth factor-β1 (TGF-β1) is a crucial mediator of fibrosis by activating downstream small mother against decapentaplegic (Smad) signaling which triggers pro-fibrotic genes overexpression. Smad3 is the major downstream regulator that promote TGF-β mediated tissue fibrosis, while Smad7 protects against fibrosis inhibiting the TGF-β1/Smad pathway. The renin-angiotensin system (RAS) also controls the fibrotic process. Marta Iannuccelli SIGNOR-FIIA FLT3-ITD in AML fcortellessa SIGNOR-FIS FLT3-ITD signaling SIGNOR-FM One-carbon Metabolism One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine) and epigenetic maintenance. Livia Perfetto SIGNOR-FSGS Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults. Gianni Cesareni SIGNOR-G Glycogenesis Glycogenesis is the process of glycogen synthesis. Glycogen is a polymer of glucose residues that is linked by α-1,4 and α-1,6 glycosidic bonds. Glycogenin initiates the process by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) utilises UDP-glucose as the glucosyl donor and elongates the glucose oligossacharide primer. Glycogen branching enzyme 1 (GBE1) generates α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Marta Iannuccelli SIGNOR-G1-S_trans Cell cycle: G1/S phase transition Cell cycle progression is a tightly regulated process that depends on the expression and activation of positive and negative regulators of the cell cycle machinery. The primary G1/S cell cycle checkpoint controls the commitment through the G1 phase to enter into the DNA synthesis S phase. Before the passage of the restriction point, activation of CCND- and CCNE-dependent CDKs initiates a sequence of events that eventually leads to the initiation of a full cell cycle. Under favorable growth conditions, CDK4/6 associate with CCNDs, phosphorylate and inactivate pRB, allowing the release of E2F and the transcription of its target genes. Under stress conditions (e,g DNA damage), the activity of CDKs can be blocked by natural inhibitors, CKI, belonging either to the INK4 or the CIP families, resulting in cell cycle arrest. Livia Perfetto SIGNOR-G2-M_trans Cell cycle: G2/M phase transition Cell cycle progression is a tightly regulated process that depends on the expression and activation of positive and negative regulators of the cell cycle machinery. The term 'cell-cycle checkpoint' refers to mechanisms by which the cell actively halts progression through the cell cycle until it can ensure that an earlier process, such as DNA replication or mitosis, is complete. The G2 checkpoint (also known as the G2/M checkpoint) prevents cells from initiating mitosis when they experience DNA damage during G2, or when they progress into G2 with some unrepaired damage inflicted during previous phases (S or G1). 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 degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary (Kastan and Bartek, 2004). Livia Perfetto SIGNOR-GBM Glioblastoma Multiforme Glioblastoma Multiforme (GBM) is one of the most common and aggresive type of brain cancers. Ninetyseven percent of tumors belong to the 'classical' subtype, and carry extra copies of the epidermal growth factor receptor (EGFR) gene, and most have higher than normal expression of epidermal growth factor receptor (EGFR), whereas the gene TP53, which is often mutated in glioblastoma, is rarely mutated in this subtype. Downstream signaling of many RTKs, including EGFR, lead to activation of the PI3K/AKT/mTOR and RAS/RAF/MAPK secondary messenger systems. Dysregulation of these intracellular signaling pathways often occurs in GBM.PTEN is an endogenous inhibitor of PI3K and RAS, and it is often lost or mutated in GBM. Other signaling molecules in the PI3K and RAS pathways are also commonly mutated in GBM. These alterations further contribute to inappropriate P13K and RAS activity in GBM. Livia Perfetto SIGNOR-GCR Glucocorticoid receptor Signaling Glucocorticoids are steroid hormones involved in various metabolic and homeostatic functions. They are synthesized by the adrenal cortex and their physiological and pharmacological actions are mediated through binding with the glucocorticoid receptor (GR). The glucocorticoid receptor, also known as NR3C1, translocates in the nucleus and modulates, positively or negatively, the transcription of thousands of genes by direct binding to DNA response elements and/or by physically associating with other transcription factors. Federica Ferrentino SIGNOR-Glycogenolysis Glycogenolysis Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase (Wikipedia) Gianni SIGNOR-Glycolysis Glycolysis and Gluconeogenesis Marta Iannuccelli SIGNOR-GP Glutamine metabolism Gianni SIGNOR-GS Glutamatergic synapse Glutamate receptors (GluRs) are the major excitatory receptors in the brain and induce depolarization of the postsynaptic membrane following the presynaptic release of glutamate. They can be classified in ionotropic and metabotropic receptors. Ionotropic GluRs are ligand-gated cation channels and can be divided in 3 groups according to their sensitivity to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), Kainate, and N-Methyl-D-aspartic acid (NMDA). AMPA receptors (GluR1-4) evoke fast excitatory postsynaptic potentials while Kainate receptors (GluR5-6 and KA1-2) and NMDA receptors (NR1-3) mediate slower synaptic transmission and exert effects also on synaptic plasticity. Glutamate can modulate neuronal excitability and synaptic transmission also through second messenger signaling pathways; mGluRs are G protein-coupled receptors that function as constitutive dimers and mediate slow synaptic potentials. Marta Iannuccelli SIGNOR-GSP GABAergic synapse Gamma aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the mammalian central nervous system (CNS). GABA binds to ionotropic GABA(a) receptors that mediate fast GABA responses by triggering chloride channel openings and metabotropic GABA(b) receptor that trigger slower responses by activating G-proteins and influencing second messenger systems. Glycine exerts its inhibitory effects via specific glycine receptors (GlyRs) anion channel and the resulting influx of Cl− ions hyperpolarizes the postsynaptic cell, thereby inhibiting neuronal firing. Marta Iannuccelli SIGNOR-HC Hippo in cancer miannu SIGNOR-Hedgehog Sonic Hedgehog Hedgehog (Hh) signaling is fundamental during embryonic patterning and postnatal physiology. During development embryonic cells require a proper secretion and gradient diffusion of the vertebrate Hedgehog-family ligands, including Sonic, Desert, and Indian Hedgehog target genes. SIGNOR-HPP Hippo Signaling The Hippo pathway controls organ size in diverse species by regulating cell proliferation, apoptosis, and stem cell self renewal. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Milica Marinkovic SIGNOR-HT Hepatocellular Tumor Hepatocellular carcinoma (HCC) is one of the most common primary malignant neoplasma of the liver, anche one of the most widespread tumors in the world with a poor prognosis. Hepatocarcinogenesis is a complex and multistep process, infact numerous signaling modules are compromised and they’re the cause of the tumor’s development and progression. Among these, the pathways that involve growth factors, such us insulin-like growth factor (IGF) or hepatocyte growth factor (HGF) are frequently found mutated in patients. Also HCC is characterized by an aberrant activation of the WNT signaling pathway. In vitro study has demonstrated that NRF2 activation preserves tumor cells from toxic exposure to reactive oxygen species and subsequent death, infact this protein promotes the expression of the anti-oxidant response genes (NQO1, HMOX1 and GSTA1). TERT promoter mutation are involved at the last step of malignant transformation; infact 90% of human HCCs harbor an increased telomerase expression. Most of the time,TERT mutations are correlated with CTNNB1 mutations, suggesting cooperation between telomerase maintenance and b-catenin pathway in liver tumorigenesis. In particoular lots of patients with HCC have got inactivating mutations of ARID1A/B (3%-18%), underlining the key role of SWI/SNF chromatin remodeling complexes as tumor suppressors; on the other hand, towards the last stages of the disease, MYC and AKT activation partecipate to improve the proliferation (in approximately 50% of HCCs). Luana Licata SIGNOR-IIS Innate Immune Response The innate immune response pathway is activated in response to pathogens by sensing molecules that reside in the cytoplasm of host cells. Once these sensors are activated, they interact with the mitochondrial membrane protein MAVS (mitochondrial antiviral) which in turn stimulates the activation of the TBK1 and IKKɛ kinases. Once activated, these kinases upregulate the activity of crucial transcription factors including interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Both IRF3 and NF-kB synergistically promote the immune response and the production of type I interferons (IFN-Is). Several viral and bacterial proteins have been shown to modulate this response. Marta Iannuccelli SIGNOR-IL1R IL1 Signaling Interleukin-1 (IL-1) is a proinflammatory cytokine produced by activated macrophages, endothelial cells, B cells and fibroblasts. IL-1 play a central role in inflammation and host defence against infection. The signalling pathways involve two adapter proteins, MyD88 and Tollip, which via two IL-1 receptor-associated kinases (IRAK and IRAK-2) activate transcription factors such as nuclear factor-kappa B. Elena Santonico SIGNOR-IL6 IL6 Signaling IL(Interleukin)-6 is a pleiotropic cytokine playing a role in many physiological and pathological processes, including inflammation, hematopoiesis, and oncogenesis It participates in the regulation of cell growth, gene activation, proliferation, survival, and differentiation. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-1 (CTF1), ciliary neurotrophic factor (CNTF) etc. all of which initiate signaling through a signal transducing receptor (gp130, LIFR, OSMR). IL-6, IL-11 and CNTF first bind specifically to their respective non-signaling α-receptor subunits that are involved in recognition of the IL-6-type cytokines (IL-6Rα, IL11Rα, and CNTFRα). IL-6 stimulates homodimerization of gp130/IL6ST resulting in the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription). Other cytokines of the family (e.g., LIF, CTF1, CNTF, OSM) stimulate heterodimerization of LIFR and gp130. The signal transducing chains gp130, LIFR and OSMR binds to JAK1, JAK2 and TYK2 . Among these, JAK1 plays an essential role in IL6 signalling. All IL-6-type cytokines potently activate STAT3, and STAT1. SOCS proteins are the feedback inhibitors. SOCS1 and SOCS3 are functionally related and inhibit IL-6-type cytokine signalling. Gp130 is ubiquitously expressed and the specific cell response to a given IL-6 type cytokine, is the result of the restricted expression of the other receptor subunits (the alfa -receptor). Livia Perfetto SIGNOR-Inflammosome Inflammosome Activation [from Wikipedia] Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses.[1][2] Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of Gasdermin-D.[2][3] The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane. Marta Iannuccelli SIGNOR-INSR Insulin Signaling In physiological conditions, insulin controls critical energy functions such as glucose and lipid metabolism. Insulin binds and activates the insulin receptor tyrosine kinase (IR), which phosphorylates and recruits different substrate adaptors. Tyrosine phosphorylated substrates, in turn, act as scaffolds for numerous partners, initiating a signaling cascade that involve via PI3K/Akt and Ras/MAP kinase pathways. SIGNOR-IOA Inhibition of Apoptosis Apoptosis needs to be tightly regulated. Survival signals such as growth factors activates pathways that inhibit pro-apoptotic proteins and activates anti-apoptotic factors. Alessandra Silvestri SIGNOR-IoT Initiation of Translation Translation initiation is a complex sequence of events required to start protein synthesis. This process requires the initiator tRNA (Met-tRNAi), the small (40S) and the large (60S) ribosomal subunits to assemble into an 80S ribosome at the initiation codon of mRNA (AUG) and is supported by eukaryotic initiation factors (eIFs). Briefly, the cap-binding complex eIF4F and the factors eIF4A and eIF4B are required for binding of 43S complexes (comprising a 40S subunit, eIF2/GTP/Met-tRNAi and eIF3) to the 5′ end of capped mRNA but are not sufficient to promote ribosomal scanning to the initiation codon. eIF1A enhances the ability of eIF1 to dissociate aberrantly assembled complexes from mRNA, and these factors synergistically mediate 48S complex assembly at the initiation codon. Joining of 48S complexes to 60S subunits to form 80S ribosomes requires eIF5B, which has an essential ribosome-dependent GTPase activity and hydrolysis of eIF2-bound GTP induced by eIF5. lperfetto SIGNOR-IS Integrin Signaling (from Wikipedia) Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor.[19] In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules. The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. [...] Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience: cell growth, cell division, cell survival, cellular differentiation, and apoptosis. Marta Iannuccelli SIGNOR-LBC Luminal Breast Cancer Breast cancer is the most frequently occurring cancer in women in the developed world, with oestrogen receptor (ER)-positive disease representing around two- thirds of all cases. In this model we focus on ER-positive/HER2- negative breast cancer who results from mutations in four main signalling pathways: 1)PI3K/AKT/mTOR pathway; 2)cyclin D1 complex/Rb/E2F pathway; 3)TP53/MDM2 pathway; and 4) FGFR1 pathway. Genes from the PI3K/AKT/mTOR pathway are the most frequently mutated in luminal breast cancer; PI3K mutations are the most prevalent mutations and are identified in around 40% of cases; In luminal tumours, inhibition of the Rb protein is mediated through CCND1 (the gene coding for cyclin D1) or CDK4 amplification or overexpression, or loss of the endogenous CDK inhibitors (CDKN2A), these muatations prevent the inactivation of the E2F transcription factor, thus leading to cell cycle progression from G1 to S phase. The TCGA showed amplification of CCND1 in 29% of patients with luminal A tumours and in 58% of patients with luminal B tumours. Moreover, two-thirds of luminal B tumours may have defective p53 pathways, either through TP53 mutations or MDM2 amplification. Finally, FGFR signalling through FGF ligand dependent or independent activation has been implicated in oncogenesis, angiogenesis and treatment resistance in various tumour types. Indeed, FGFR1 amplification has been found in up to 10% of breast cancer tumours. Livia Perfetto SIGNOR-LR Leptin Signaling Marta Iannuccelli SIGNOR-M1M2 Macrophage polarization Macrophages constitute a very heterogeneous population of phagocytic cells, involved in immune-related and non-immune related processes and therefore, depending upon their immediate environment, can have very distinct phenotypes. One of the most popular classification divides activated macrophages into 2 categories: M1, known as “pro-inflammatory” and M2, known as “anti-inflammatory” macrophages. M1s are induced by IFNg, microbial stimuli (such as PAMPs), or cytokines, while M2s are induced by IL4, Il10 and IL13. Alessandro Palma SIGNOR-MC mTOR in cancer miannu SIGNOR-MCAPO Mitochondrial Control of Apoptosis Apoptosis is a type of programmed cell death that allows the maintenance of cellular homeostasis. Mitochondrial membrane permeabilization represents a critical step in the regulation of intrinsic apoptosis, process that is mainly regulated by members of the Bcl2 family of proteins that can act as pro- or anti-apoptotic factors. Alessandra Silvestri SIGNOR-MD Mitochondrial dynamics in T cell exhaustion This pathway weaves together T cell activation pathways with regulators of mitochondrial dynamics (fission and fusion). It depicts the dynamic interplay between these molecular components, highlighting the orchestrated communication between T cell activation machinery and the regulation of mitochondrial morphology. The network's unique feature is its culmination, where specific nodes interacting with a tumor cell lead to the phenomenon of T cell exhaustion. This representation provides an insight into the molecular intricacies of T cell activation and mitochondrial dynamics unraveling the regulatory mechanisms triggering T cell exhaustion in response to tumor interactions. Hesham SIGNOR-MM Malignant Melanoma Melanoma is a skin cancer. It might exist as distinct subtypes associated with the activation of the MAPK and the PI3K pathways even if there is an association between distinct melanoma subtypes and molecular somatic events. Mucosal, acral, and to a lesser extent, lentigo malignant melanomas, can have increased copies of CDK4, and CCND1 (cyclinD), as well as mutations in KIT receptor. NRAS is mutated in about 18% of melanomas, and seems to be more frequently activated in nodular melanomas and melanomas due to chronic sun damage. BRAF has a recurrent V600E mutation (Gain of function) in about 50–70% of melanomas, however, this mutational event is frequently reported in benign pigmented naevi, and is not fully sufficient to induce a malignant transformation. MEK1 and MEK2 are downstream from RAS and RAF, on the same MAPK pathway. Activating mutations of MEK1 and MEK2 are found in 8% of melanomas. The PI3K pathway is activated through a PTEN loss-of-function mutation (most often deletion) in 20–40% of melanomas. Activating mutations or amplifications of PI3K or of AKT1 can also be found in some melanomas. Livia Perfetto SIGNOR-mRNA_Maturation mRNA maturation Livia Perfetto SIGNOR-MS MTOR Signaling The mammalian target of rapamycin (mTOR) signaling pathway couples energy and nutrient abundance to cellular growth. mTor is serine/threonine kinase acting in two complexes (mTORC1 and mTORC2) which exert their actions by regulating other important kinases, such as S6K and Akt. In particular, mTORC1 integrates multiple signals reflecting nutrients' availability or deprivation promoting cellular growth or catabolic processes respectively. SIGNOR-MSP Multiple sclerosis Marta Iannuccelli SIGNOR-Myogenesis IGF and Myogenesis Skeletal myogenesis is the process of formation of the muscles that enable movement and breathing. Being an extraordinarily complex process, myogenesis is regulated at multiple levels, and transcriptional regulation naturally plays a big part during muscle formation. Milica Marinkovic SIGNOR-NFKBC NF-KB Canonical The NF-kB family of transcription factors plays important roles in the immune system. Two signaling pathways lead to the activation of NF-kB, known as the classical (canonical) pathway and the non-canonical (alternative) pathway. The common regulatory step is activation of an IkB kinase (IKK) complex consisting of catalytic kinase subunits (IKKalpha and/or IKKbeta) and the regulatory non-enzymatic scaffold protein NEMO (NF-kB essential modulator also known as IKKgamma). Activation of NF-kB dimers is due to IKK-mediated phosphorylation-induced proteasomal degradation of IkB, enabling the active NF-kB transcription factor subunits to translocate to the nucleus and induce target gene expression. The canonical NF-kB pathway is induced by several signals including antigens, TLR ligands and cytokines such as TNF. It uses a wide variety of signaling adaptors to engage and activate the IKKbeta subunit of the IKK complex. IKKbeta phosphorylation of classical IkB proteins bound to NF-kB dimers such as p50-p65 results in ubiquitination (Ub) of IkB and proteasome-induced degradation. Elena Santonico SIGNOR-NFKBNC NF-KB Non Canonical The non-canonical pathway engaged by members of the TNF-like family of cytokines is responsible for the activation of p100/RelB complexes and occurs during the development of lymphoid organs responsible for the generation of B and T lymphocytes. This pathway utilizes an IKK complex that comprises two IKKalpha subunits, but not NEMO. 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. Elena Santonico SIGNOR-NM Nucleotide Biosynthesis Marta Iannuccelli SIGNOR-NOTCH NOTCH Signaling Notch signaling is a highly conserved system of intracellular comunication, which is highly conserved in evolution, It plays a key role in embryonic development, stem cell differentiation, apoptosis and cell migration. Daniela Posca SIGNOR-NOTCH_Myogenesis NOTCH Signaling and Myogenesis Signaling induced by interaction between the receptor Notch and its ligand Delta plays an important role in cell fate determination in vertebrates. Notch signaling has emerged as a key player in skeletal muscle development and regeneration, where it inhibits muscle differentiation. Protein products of the Notch target genes repress transcription of pro-myogenic genes, activated by MyoD and Mef2C, through multiple mechanisms, including targeted repression by Hey1. SIGNOR-NPM1-FLT3-DNMT3A Triple mutant AML miannu SIGNOR-NPM1_new NPM1_new marta iannuccelli SIGNOR-NR Neurotransmitters release Presynaptic active zones consist of a highly specialized network of proteins that acts in neurotransmitter release. The key function of the active zone is to organize the fusion process that is mediated by SNARE proteins and triggered by calcium to render it highly temporally and spatially precise. Marta Iannuccelli SIGNOR-NS Noonan syndrome Noonan syndrome is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations.Mutations in the PTPN11 gene cause about half of all cases. SOS1 gene mutations cause an additional 10 to 15 percent, and RAF1 and RIT1 genes each account for about 5 percent of cases. Gianni Cesareni SIGNOR-NSCLCN Non-small-cell lung cancer (NSCLC) Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer (approximately 85%). Luana Licata SIGNOR-OS Oxytocin signaling Marta Iannuccelli SIGNOR-P38 P38 Signaling This representation depicts some of the pathways leading to p38/MAPK14 activation during inflammation or upon TGF-beta stimulation. P38 is activated also in other circumstances such as DNA damage, heat shock, osmotic stress or myogenesis. Andrea Cerquone Perpetuini SIGNOR-P38_Myogenesis P38 Signaling and Myogenesis Starting from pro-myogenic stimuli such as TNFa or cell-to-cell contact and passing through the signalling cascade down to the key transcription factors involved in muscle differentiation, the pathway illustrates the main players involved in the regulation of myogenesis mediated by p38/MAPK14. Andrea Cerquone Perpetuini SIGNOR-PC Prostate Cancer Prostate cancer (PC) is the most common male tumor. Usually is an indolent disease but about 30% of cases become aggressive; in case of metastatic cancer, about 70-80% of patients respond to androgen-deprivation therapy, but in later stages PC becomes hormone-independent and more aggressive resulting in the second cause of all male cancer deaths. PC is an heterogeneous and complex disease; it could be divided in two categories based on the presence/absence of genomic rearrangements that place proteins of the ETS transcription factor family, frequently ERG, under control of androgen responsive promoter TMPRSS2. Increased expression of ETS factors under control of AR promoter activates transcriptional program that contributes to oncogenesis by upregulating MYC and EZH2 proteins and repressing NKX3.1 ETS fusion proteins are found in 60% of PC, and the fusion-negative category could be divided into several subtype group. The most studied genomic alterations in PC affect : • the androgen receptor (AR) signalling pathway: AR plays a crucial role in the early development of PC and in its progression because of the lead role of androgen receptor transcriptional program in prostate epithelium cells. • PTEN mutations and/or deletions: PTEN is a phosphatase that acts as a tumor suppressor downregulating the PI3K-AKT signaling pathway which is essential for cell cycle progression and cell survival. • loss of function mutation of the tumor suppressor NKX3.1: this is an early event in prostate carcinogenesis. NKX3.1 and AR directly regulate each other in a loop and, together with FOXA1, are important regulators in PC progression. • point mutations in SPOP are common in primary PC. SPOP binds and promotes the degradation of SRC-3, an AR cofactor, whereas SPOP mutants lose this ability, leading to upregulated androgen signaling. Marta Iannuccelli SIGNOR-PCP p53 in cancer Marta Iannuccelli SIGNOR-PD Parkinson Parkinson disease (PD) is a neurodegenerative disorder, whose clinical manifestations include resting tremor, muscular rigidity and akinesia. PD is associated to the selective degeneration and death of dopaminergic neurons and is characterized by the deposition of abnormal protein aggregates called “Lewy bodies” in the surviving dopaminergic neurons. Alpha-synuclein is a major protein component of Lewy bodies and is found to be mutated or over-expressed in patients with PD. Other proteins that have been found to be mutated or over-expressed in PD are: Parkin, it is an E3 ubiquitin ligase that, in normal condition, ubiquitinates alpha-synuclein with its consequent proteasome-dependent degradation, mutations in Parkin gene lead to accumulation of alpha-synuclein; UCH-L1 is an Ubiquitin hydrolase that generates Ubiquitin monomers, necessary for the degradation of alpha-synuclein, mutant forms of UCH-L1 result in accumulation of alpha-synuclein; Mutations in DNAJC14 genes are associated with increased level of oxidative stress that predispose neurons to precipitate alpha-synuclein. Livia Perfetto SIGNOR-PDAP Pancreatic ductal adenocarcinoma (PDA) Pancreatic ductal adenocarcinoma (PDA) is the predominant form of pancreatic cancer. It is particularly heterogeneous. Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors. The overexpression of HER-2/neu and activating point mutations in the KRAS gene occur early, inactivation of the CKN2A gene (p16INK and p19ARF) at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Also RAF mutations are found, but BRAF and KRAS gene mutations are mutually exclusive. Other mutated oncogenes are AKT1 or AKT2. Other tumor suppressors: CDKN2B and FHIT. Luisa Castagnoli SIGNOR-PGC PPARgamma in cancer Marta Iannuccelli SIGNOR-PI3K-AKT PI3K/AKT Signaling (From Wikipedia) The Akt Pathway, or PI3K-Akt Pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. [...] Initial stimulation by one of the growth factors causes activation of a cell surface receptor and phosphorylation of PI3K. Activated PI3K then phosphorylates lipids on the plasma membrane, forming second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Akt, a serine/threonine kinase, is recruited to the membrane by interaction with these phosphoinositide docking sites, so that it can be fully activated. Activated Akt mediates downstream responses, including cell survival, growth, proliferation, cell migration and angiogenesis, by phosphorylating a range of intracellular proteins. The pathway is present in all cells of higher eukaryotes and is highly conserved. gcesareni SIGNOR-PPP Pentose phosphate pathway SIGNOR-PU Ubiquitin activation Marta Iannuccelli SIGNOR-RAM Retinoic Acid Metabolism In the blood, serum retinol (Vitamin A) travels in association with RBP4 and enters the cells by membrane transport through STRA6 membrane transporter. Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to RBP1, which plays a role in vitamin A cytoplasmic trafficking. Inside the cell, retinol undergoes the 2-steps oxidative pathway to generate all-trans retinoic acid (RA). In this case, the conversion of retinol into retinal is performed by the Retinol dehydrogenase (RDH) whereas the second oxidative step is the irreversible conversion of retinal into RA, catalyzed by Retinaldehyde dehydrogenase (RALDH). RA is finally transferred into the nucleus by RBP2 to act as a signaling molecule. RA intracellular levels must be tightly controlled to maintain the appropriate CYP26A1 degrades the excess of RA. Livia Perfetto SIGNOR-RAS Retinoic acid Signaling Retinoic Acid (RA) promotes neurogenesis by regulating the switch between proliferation and differentiation. RA binds to retinoic acid receptors (e.g. RARA, RARB and RARG) which in turn bind and activate coreceptor RXRA. RXRA downstream effects include inhibition of proliferation, inhibition of NOTCH and the restoring of expression of neurogenic genes such as NEUROG1 and NEUROG2. Livia Perfetto SIGNOR-ReS Rett syndrome Luana SIGNOR-RMS Rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a relatively rare cancer but is the most common form of soft-tissue sarcomas in young adults children and children. RMS can originate as a consequence of myogenic precursors failing to differentiate into normal muscle and is characterised by two major subtypes, embryonal RMS (ERMS) and alveolar RMS (ARMS). ERMS is the most common form of the disease, comprises about 60% of cases, and has a more favourable outcome than ARMS. It’s characterized by a wide range of genetic aberrations and the most frequent is the loss of heterozygosity at the 11p15 locus, a region that encodes insulin-like growth factor 2 (IGF2). ARMS is the most aggressive form of RMS with a poorer prognosis and more prone to metastasis. It’s characterized by genetic translocations that result in chimeric protein that fuse the DNA binding domain of the paired box proteins 3 or 7 (PAX3 or PAX7) to the transactivation domain of a forkhead transcription factor (FOXO1). RMS display many defects in growth-factor signalling pathways and cell-cycle checkpoints that lead to cell growth and proliferation. The most frequently affected pathways are fibroblast growth factor (FGF), insulin-like growth factor (IGF), hepatocyte growth factor, and platelet-derived growth factor. PAX-FOXO1 proteins can activate these pathways by transcriptional activation of IGFR1, FGFR4, MET (c-Met) and PDGFRA genes. In 93% of RMS cases there is an alteration of the receptor tyrosine kinase/RAS/ PI3K axis and that alterations appeared to hinge on the FGF and IGF pathways. FGF and IGF pathways converge on cell-cycle regulators such as the cell-cycle regulator p21 (CDKN1A), and the cell-cycle regulator p14 (CDKN2A). p21 is induced in myoblast differentiation and blocks cell-cycle progression ; is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these proteins in RMS contributes to the silencing of p21. p14 is tumour suppressor and copy number deletions in CDKN2A were found in 2% of the RMS cancers. TBX2, a T-box gene family member, is overexpressed in both ERMS and ARMS cells. it is regulated by PAX3 and was found to induce a downregulation of p14 and to be a direct repressor of p21 in RMS. Marta Iannuccelli SIGNOR-RS RTKs in cancer miannu SIGNOR-SAPK-JNK SAPK/JNK Signaling Stress-activated protein kinases/c-Jun NH(2)-terminal kinases (SAPK/JNK) proteins are MAPK family members that are activated by several extracellular signals (i.e. inflammatory cytokines and growth factors) and cellular stress. When activated by cellular stress the SAPK/JNK pathway induces cell death by apoptosis. The SAPK/JNK pathway also plays a physiological role in embryonic development by regulating cell survival, apoptosis, and proliferation. Daniela Posca SIGNOR-SARS-COV-APOPTOSIS SARS-COV APOPTOSIS Apoptosis is the programmed cell death process activated under cellular stress conditions and characterized by an extremely organised disassembly of cellular structures. Two are the main pathways activated during apoptosis: the intrinsic pathway that involves Bcl2 family proteins and the extrinsic pathway, involving the cascade of the death ligands (such as FasL and TNF-α). The extopic expression of several HCoVs, such as S, E, M, N, 3a, 3b, 6, 7a and 8a promotes apoptosis in infected cells. The molecular mechanisms are poorly characterized. In addition, in HCoV-infected cells, caspase-dependent apoptosis processes are induced and modulated by the activation of the mitogen-activated protein kinase (MAPK) pathway. Luana SIGNOR-SARS-CoV-MAPK-Pathway SARS-CoV MAPK PERTURBATION Serine/threonine protein kinases MAPKs are activated following several different environmental stimuli, such as DNA damage, heat shock or pro-inflammatory cytokines. Typically MAPKs, by phosphorylating their protein substrates, regulate numerous crucial cellular processes such as proliferation, apoptosis, and immune response. This pathway describes the activation of p38, ERK, and JNK signalling occurring during Human coronavirus proteins (HCoV) infection. Activated p38 can directly or indirectly phosphorylates a wide variety of substrate proteins, including important transcription factors such as CREB, ATF2, AP1 and CHOP. Several studies have demonstrated p38 activation in Vero E6 cells infected with SARS-CoV. Similar to p38, phosphorylation of ERK and upstream kinases MKK1/2 has been observed in A549 and Vero E6 cells upon SARS-CoV infection. Likewise, phosphorylation of JNK and its upstream kinases MKK4 and MKK7 was observed in Vero E6 cells infected with SARS-CoV. Recent studies have demonstrated the involvement of Growth Factor Receptors signalling in the activation of MAPK signalling cascade during HCoV infection. This pathway also shows how the ectopic expression of HCoV proteins, such as E, N, 3a, 3b, 7a can promote p38, JNK and ERK1/2 activation. Luana SIGNOR-SCAAE SARS-CoV ATTACHMENT AND ENTRY SARS-CoV2 engages angiotensin-converting enzyme 2 (ACE2) as a receptor for viral attachment to the target cell surface. Entry requires priming of the S protein by the cellular serine protease TMPRSS2 and the endosomal cysteine proteases cathepsin B and L (CatB/L), which cleave S protein at the S1/S2 sites, allowing specific interaction between S1 and ACE2 receptor. When SARS-CoV2 binds ACE2, it is internalized by clathrin-dependent endocytosis or by direct membrane fusion of viral and cellular membranes. Binding of the Spike protein to ACE2 suppresses the expression of the receptor by increasing internalization and shedding from the cell surface. The decreased expression of ACE2 and the consequent reduction of Ang1–7 leads to the downregulation of the Ang1–7-receptor Mas1. Mas1 modulates the inflammatory response and activates a signalling cascade regulating the IRF3-mediated stimulation of the immune response. Marta Iannuccelli SIGNOR-SCCS SARS-CoV CYTOKINE STORM Inflammation is an essential part of the immune response. Unfortunately, SARS-CoV-2 infection induces a massive and prolonged inflammatory responses in some patients, known as “cytokine storm”. Cytokine storm results from the effects of a combination of several immune-active molecules: interferons, chemokines, interleukins (eg Interferon γ, interleukin IL-1B, IL-6, IL-12, CXCL10, CCL2 and TNF-alpha) represent the main components involved in its development. The uncontrolled production and secretion of these factors cause a massive and generalized inflammatory response that could culminates into ARDS (acute respiratory distress syndrome) or acute lung injury, two clinical conditions with high mortality rate. Efficent control of the cytokine storm is the key to improving the treatment success and reducing the mortality rate of patients with COVID-19. Marta Iannuccelli SIGNOR-SCFI SARS-CoV FIBROSIS Pulmonary fibrosis is a common consequence of SARS coronavirus (SARS-CoV) infection. Transforming growth factor-β1 (TGF-β1) is a crucial mediator of this phenomenon and causes tissue fibrosis by activating downstream small mother against decapentaplegic (Smad) signaling which triggers pro-fibrotic genes overexpression. Smad3 is the major downstream regulator that promote TGF-β mediated tissue fibrosis, while Smad7 protects against fibrosis inhibiting the TGF-β1/Smad pathway. The renin-angiotensin system (RAS) also controls the fibrotic process. The Spike-dependent down-regulation of ACE2 receptor decreases the Ang (1-7) level, upregulating the angiotensin-converting enzyme (ACE)- Ang II-angiotensin type 1 receptor (AT1R) signalling cascade, which in turn triggers inflammation and fibrosis in pulmonary tissue. Marta Iannuccelli SIGNOR-SCIR SARS-CoV INFLAMMATORY RESPONSE An innate immune response against SARS-CoV infection is triggered by the recognition of pathogen-associated molecular patterns (PAMPs, dsRNA) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). Activated receptors recruit adaptor proteins, which trigger the activation of multiple kinases, ultimately activating transcription factors including interferon regulatory factor3 (IRF3) and nuclear factor kappa- light-chain-enhancer of activated B cells (NF-κB). NF-kB promotes the production of type I interferons (IFN-I), which are released and bind the IFN-α/β receptor (IFNAR) expressed on the surface of other cells. This inflammatory response to SARS-CoV infection represents the first line defense against the virus. Coronaviruses interfere with several steps of the immune response, including RNA sensing, type I IFN production and IFN dependent signaling. Marta Iannuccelli SIGNOR-SCISOVG SARS-CoV INNATE RESPONSE TO dsRNA Double-stranded RNA (dsRNA) is generated during replication of positive -strand RNA and DNA viruses. The innate immune response pathway is activated in response to HCoV infection by dsRNA-sensing molecules that reside in the cytoplasm of host cells. Once these sensors are activated, they interact with the mitochondrial membrane protein MAVS (mitochondrial antiviral) which in turn stimulates the activation of the TBK1 and IKKɛ kinases. Once activated, these kinases upregulate the activity of crucial transcription factors including interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Both IRF3 and NF-kB synergistically promote the immune response and the production of type I interferons (IFN-Is). Several viral proteins have been shown to modulate this response. The molecular mechanisms however are not understood Marta Iannuccelli SIGNOR-SCSG SARS-CoV STRESS GRANULES Viral genes expression is impeded by activation of cellular stress responses like global inhibition of protein translation and formation of stress granules (SGs). Stress granules are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Their formation lead to translational repression, and stress granules actively signal to maintain translational block, activates innate immunity response, and repress apoptosis. Ras-GTPase-activating protein SH3 domain-binding protein 1/2 (G3BP1, G3BP2) initiate the assembly of SGs by forming homo-multimer and hetero-multimer with each other. La-related protein 4B (LARP4B) is another cytosolic protein that accumulates in stress granules. Under physiological conditions, LARP4B interacts with the cytosolic poly(A) binding protein 1 (PABPC1) and the receptor for activated C Kinase (RACK1), a component of the 40S ribosomal subunit and activates translation. So, its recruitment in SGs and sequestration of a large number of cellular mRNAs directly contribute to the general translation inhibition. Marta Iannuccelli SIGNOR-SCUP SARS-CoV ER STRESS Coronavirus uses endoplasmic reticulum (ER) as a site for synthesis and processing of viral proteins. During HCoV infection, viral structural proteins, in particular the S glycoprotein, are produced in massive amounts saturating the ER folding capacity. Thus, unfolded proteins accumulate in the ER triggering an unfolded protein response (UPR). The UPR is mediated by three ER-resident transmembrane proteins PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE-1) and alleviates the stress both by globally attenuating translation and by up-regulating genes facilitating protein folding and degradation. Marta Iannuccelli SIGNOR-SHB Sex Hormone Biosynthesis The sex Hormone Biosynthetic pathway (also called Steroidogenesis) is an enzymatic cascade by which cholesterol is converted to biologically active steroid hormones. The first (rate-limiting) enzymatic step consists in the conversion of cholesterol into pregnenolone by P450 side chain cleavage (CYP11A1). Pregnenolone can subsequently be converted into progesterone by 3-beta-hydroxysteroid dehydrogenase (HSD3B1 and HSD3B2) or into 17-hydroxypregnenolone by 17-alpha-hydroxylase/17,20 lyase (CYP17A1). Then, CYP17A1 can convert progesterone into 17-hydroxyprogesterone, whereas HSD3B1 can convert 17-hydroxypregnenolone into 17-hydroxyprogesterone. In a next step, 17-hydroxypregnenolone and 17-hydroxyprogesterone can be converted by CYP17A1 into dehydroepiandrosterone (DHEA) and androstenedione, respectively. In turn, the activity of different 17beta-HSD enzymes catalyzes the synthesis of androstenediol from DHEA and testosterone from androstenedione. Aromatase converts androstenedione and testosterone into estrone and beta-estradiol, respectively. Considering glucocorticoids, the synthesis of 11-deoxycortisol and 11-deoxycorticosterone from 17-hydroxyprogesterone and progesterone, respectively, are catalyzed by 21-hydroxylase (CYP21A2), followed by the P450C11 (CYP11B1 and CYP11B2) activity leading to the synthesis of cortisol and corticosterone. Livia Perfetto SIGNOR-TA TNF-alpha Signaling The Tumor necrosis factor modulates a vast array of cell functions including inflammation, apoptosis, cell proliferation, immunity and differentiation. TNF alpha is mainly produced by macrophages. SIGNOR-TC Thyroid cancer Thyroid cancer (TC) is the most common tumor of the endocrine system. The most frequent type of TC is papillary thyroid cancer (PTC), comprising 90% of all cases. The second most common type is follicular thyroid cancer (FTC) that accounts for 10% of total. PTCs and FTCs both arise from the thyroid follicular cells and are termed differentiated thyroid cancer (DTC). Medullary thyroid cancer (MTC) instead arises from the parafollicular C cells and represents 5% of all TCs. Finally, anaplastic thyroid cancer is one of the most aggressive TCs and can arise from DTCs that dedifferentiate or it can develop de-novo. Ionizing radiation is the only exogenous factor which has been identified as causing TC, mostly the papillary form. PCs frequently have genetic alterations leading to the activation of the MAPK signaling pathway like point mutations of the BRAF and RAS genes and RET/PTC rearrangement. BRAFV600E results in the constitutive activation of this serine/threonine kinase and occurs in approximately 45% of PTCs. Gene translocations resulting in oncogenic rearrangements in PC are best exemplified by more than 10 types of RET–PTC translocations resulting in oncoproteins that activate the MAPK and PI3K–AKT pathways. Most frequent alterations in FC include RAS mutations and PAX8-PARγ rearrangement. Point mutations of RET receptor are crucial for the development of medullary carcinomas. Many of these mutations, particularly those involved in the activation of the MAPK pathway, are being explored as therapeutic targets for thyroid cancer. Marta Iannuccelli SIGNOR-TCA T cell activation (From Wikipedia) T cells utilise the Src family kinases in transmembrane signalling largely to phosphorylate tyrosines that are part of immunoreceptor tyrosine-based activation motifs (ITAM) in intracellular parts of CD3 and ζ chains. Early signaling steps implicate the kinases lck an Fyn and Zap70 and the phosphatase CD45 after TCR triggering: When a T-cell receptor is activated by contact with a peptide:MHC complex, CD45 dephosphorylates inhibitory tyrosine of membrane-localized Src family kinases Fyn and Lck, previously recruited and activated by CD4 or CD8 coreceptors. Activated Fyn and Lck phosphorylates ITAMs on the CD3 and ζ chains. This allows cytoplasmic kinases of the Syk family (ZAP-70) to bind to the ITAM and activated ZAP-70 phosphorylates tyrosines on the adaptor protein LAT, which then attracts PLC-γ. Gianni SIGNOR-TEAT Translation elongation and termination Marta Iannuccelli SIGNOR-TGFb TGF-beta Signaling The transforming growth factor beta (TGF-Beta) signaling pathway is involved in many cellular processes among which, the regulation of cell growth and differentiation. So, defects in TGF-Beta signaling pathways have been linked to uncontrolled cellular proliferation and carcinogenesis. Briefly, a TGF-Beta superfamily ligand induces the heteromeric complex formation of two serine/threonine kinase receptors, type I and type II TGF-Beta receptors. The type II receptor phosphorylates the type I receptor that, once activated, in turn phosphorylates downstream R-Smad proteins (in particular Smad2 and 3), activating them to transduce the signal to the nucleus with the help of the common partner Smad4 and thus participating in the regulation of target genes expression. Other members of the SMAD family of transcriptional regulators also participate in the regulation of the TGF-Beta signaling pathway. Moreover, other signaling pathways like the MAP kinase-ERK cascade are activated by TGF-Beta signaling. Lisa Petrilli SIGNOR-THM Thyroid Hormone Metabolism Silvia Contino SIGNOR-TI Transcription initiation Initiation is the beginning of transcription. It occurs when the enzyme RNA polymerase binds to a region of a gene called the promoter. Livia Perfetto SIGNOR-TLR Toll like receptors Toll-like receptors (TLRs) play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes (PAMPs).TLRs are also involved in monitoring stress by recognizing molecules DAMPs that are released by cells under stress. SIGNOR-TSC TGFb in cancer miannu SIGNOR-VDM Vitamin-D Metabolism Vitamin D can be either be obtained from nutrition or synthesised by our body in a reaction that requires Ultraviolet radiation. Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre–vitamin D, which isomerizes to vitamin D in the skin. Vitamin D–binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. Livia Perfetto SIGNOR-VEGF VEGF Signaling From Wikipedia.Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF),[1] is a signal protein produced by cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature) Gianni SIGNOR-VKC Vitamin-K cycle Vitamin K plays an important role in blood coagulation and bone formation. Vitamin K obtained from the diet. Once transferred to the cells of the target tissue, vitamin K is metabolized by redox cycling in the intracellular endoplasmic reticulum body, in a process known as the “vitamin-K cycle”. 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). GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (coagulation factors F2,F7, F9 and F10, PROS, PROC, and bone factor Osteocalcin (BGLAP) etc…), while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. The epoxide form of vitamin K is reduced by epoxide reductase (VKORC1) to a reduced form and then to the reduced hydroquinone form. This reuse system allows for a very small amount of vitamin K in cells to act efficiently as a cofactor of GGCX in the post-translational carboxylation of VKDPs. Warfarin, an oral anticoagulant drug, inhibits VKOR, stops the vitamin K cycle, and prevents coagulation. Livia Perfetto SIGNOR-WC Wnt in cancer miannu SIGNOR-WNT WNT Signaling The Wnt signaling pathway is a conserved pathway in animals, that directs cell proliferation, cell polarity and cell fate determination during embryonic development and tissue homeostasis. The extracellular Wnt signal stimulates several intra-cellular signal transduction cascades. The three best-characterized WNT pathways are shown: the canonical or Wnt/Beta-catenin dependent pathway and the non-canonical or Beta-catenin-independent pathway, that can be divided into the Planar Cell Polarity pathway, which is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements; and the Wnt/Ca2+ pathway, which regulates the transcription of genes controlling cell fate and cell migration. Anna Mattioni SIGNOR-WNT/FLT3 WNT/FLT3 Gianni SIGNOR-WNT_Myogenesis WNT Signaling and Myogenesis Wnt ligands activate a pathway that is related to a wide range of critical cell functions (e.g. cell division, migration, and synaptogenesis) and also play a fundamental role in skeletal muscle physiology. Signaling downstream of Frizzled receptors may lead to transcriptional activation of Myf5 through a Beta-catenin dependent pathway and MyoD via a Beta-catenin independent pathway, thus initiating myogenesis.