Relation Results

Summary

Name EIF2AK2
Full Name Interferon-induced, double-stranded RNA-activated protein kinase
Synonyms Eukaryotic translation initiation factor 2-alpha kinase 2, eIF-2A protein kinase 2, Interferon-inducible RNA-dependent protein kinase, P1/eIF-2A protein kinase, Protein kinase RNA-activated, PKR, Protein kinase R, Tyrosine-protein kinase EIF2AK2, 2.7.10.2, p68 kinase | PKR, PRKR
Primary ID P19525
Links - -
Type protein
Relations 38
Pathways COVID-19 Causal Network, Innate Immune Response, Inflammosome Activation, SARS-CoV CYTOKINE STORM, SARS-CoV INFLAMMATORY RESPONSE, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
Function IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S ...
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Type: Score: Layout: SPV 
0.20.20.3310.3430.5220.5590.7210.20.20.20.3310.310.70.6260.20.70.3060.3290.3120.3170.490.465EIF2AK2SPHK1PPP2R5AIRS1NFKBIATP53EIF2S1KDM4CRPS6KA3MAPK1CDK1G3BP1Viral_dsRNADNAJC3Uridylate-specific endoribonucleaseImmune_responseNLRP1 inflammasomeNLRP3 inflammasomeNLRC4 inflammasomeAIM2 inflammasomeISGF3 complexADARB1

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▶Modifications Tables

Relations
Regulator
Mechanism
target
score ℹ
+ EIF2AK2up-regulates activity img/direct-activation.png phosphorylation SPHK1 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-278514 Ser225 VGSKTPAsPVVVQQG Homo sapiens
pmid sentence
This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2up-regulates img/direct-activation.png phosphorylation EIF2AK2 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-85765 Ser242 NQRKAKRsLAPRFDL Homo sapiens
pmid sentence
We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85769 Ser83 NKEKKAVsPLLLTTT Homo sapiens
pmid sentence
Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85773 Thr255 DLPDMKEtKYTVDKR Homo sapiens
pmid sentence
We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85777 Thr258 DMKETKYtVDKRFGM Homo sapiens
pmid sentence
We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85781 Thr88 AVSPLLLtTTNSSEG Homo sapiens
pmid sentence
Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85785 Thr89 VSPLLLTtTNSSEGL Homo sapiens
pmid sentence
Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.
Identifier Residue Sequence Organism Cell Line
SIGNOR-85789 Thr90 SPLLLTTtNSSEGLS Homo sapiens
pmid sentence
Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites.
Publications: 7 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Innate Immune Response, Inflammosome Activation, SARS-CoV CYTOKINE STORM, SARS-CoV INFLAMMATORY RESPONSE, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ EIF2AK2up-regulates img/direct-activation.png phosphorylation PPP2R5A 0.331
Identifier Residue Sequence Organism Cell Line
SIGNOR-181793 Ser28 VDGFTRKsVRKAQRQ Homo sapiens
pmid sentence
Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2down-regulates activity img/direct_inhibition.png phosphorylation IRS1 0.343
Identifier Residue Sequence Organism Cell Line
SIGNOR-278310 Ser312 TESITATsPASMVGG Homo sapiens
pmid sentence
First, PKR induces phosphorylation of IRS1 at Ser312 and suppresses tyrosine phosphorylation of IRS1, mediated by the insulin receptor substrates kinases, JNK and I\u03baB kinase.|These results suggest that PKR induces the inhibitory phosphorylation of IRS1 at Ser312 in HepG2 cells, thereby suppressing the phosphorylation at Tyr941.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2down-regulates quantity by destabilization img/direct_inhibition.png phosphorylation NFKBIA 0.522
Identifier Residue Sequence Organism Cell Line
SIGNOR-249335 Ser32 LLDDRHDsGLDSMKD
pmid sentence
As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation.
Publications: 1
Pathways:COVID-19 Causal Network, SARS-CoV STRESS GRANULES
+ EIF2AK2up-regulates img/direct-activation.png phosphorylation TP53 0.559
Identifier Residue Sequence Organism Cell Line
SIGNOR-68033 Ser392 FKTEGPDsD Homo sapiens
pmid sentence
The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2down-regulates img/direct_inhibition.png phosphorylation EIF2S1 0.721
Identifier Residue Sequence Organism Cell Line
SIGNOR-140656 Ser52 MILLSELsRRRIRSI Homo sapiens
pmid sentence
The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ EIF2AK2down-regulates quantity by destabilization img/direct_inhibition.png phosphorylation KDM4C 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-277497 Ser918 MFDDGSFsRDTFPED Homo sapiens SW-1573 Cell
pmid sentence
In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2up-regulates activity img/direct-activation.png phosphorylation EIF2AK2 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-251110 Thr446 LKNDGKRtRSKGTLR Saccharomyces cerevisiae
pmid sentence
Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer
Identifier Residue Sequence Organism Cell Line
SIGNOR-107511 Thr451 KRTRSKGtLRYMSPE Homo sapiens HeLa Cell
pmid sentence
Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer
Identifier Residue Sequence Organism Cell Line
SIGNOR-260782 Tyr101 EGLSMGNyIGLINRI in vitro
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.
Identifier Residue Sequence Organism Cell Line
SIGNOR-251112 Tyr101 EGLSMGNyIGLINRI Homo sapiens HT-1080 Cell
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation.
Identifier Residue Sequence Organism Cell Line
SIGNOR-251113 Tyr162 QLAAKLAyLQILSEE Homo sapiens HT-1080 Cell
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation.
Identifier Residue Sequence Organism Cell Line
SIGNOR-260783 Tyr162 QLAAKLAyLQILSEE in vitro
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.
Identifier Residue Sequence Organism Cell Line
SIGNOR-251114 Tyr293 HRIDGKTyVIKRVKY Homo sapiens HT-1080 Cell
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue.
Identifier Residue Sequence Organism Cell Line
SIGNOR-260784 Tyr293 HRIDGKTyVIKRVKY in vitro
pmid sentence
PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR.
Publications: 8 Organism: Saccharomyces Cerevisiae, Homo Sapiens, In Vitro
Pathways:COVID-19 Causal Network, Innate Immune Response, Inflammosome Activation, SARS-CoV CYTOKINE STORM, SARS-CoV INFLAMMATORY RESPONSE, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ RPS6KA3up-regulates img/direct-activation.png phosphorylation EIF2AK2 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-154183 Thr451 KRTRSKGtLRYMSPE Homo sapiens Skin Cancer Cell
pmid sentence
Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase.
Publications: 1 Organism: Homo Sapiens
+ MAPK1up-regulates img/direct-activation.png phosphorylation EIF2AK2 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-56337 Thr451 KRTRSKGtLRYMSPE Homo sapiens
pmid sentence
Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr.
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2down-regulates img/direct_inhibition.png phosphorylation CDK1 0.331
Identifier Residue Sequence Organism Cell Line
SIGNOR-164809 Tyr4 yTKIEKIG Homo sapiens
pmid sentence
Our findings demonstrate that (i) pkr, ser/thr kinase, phosphorylates its new substrate cdc2 at the tyr 4 residue, (ii) pkr-mediated tyr 4-phosphorylation facilitates cdc2 ubiquitination and proteosomal degradation
Publications: 1 Organism: Homo Sapiens
+ G3BP1up-regulates activity img/direct-activation.png binding EIF2AK2 0.31
Identifier Residue Sequence Organism Cell Line
SIGNOR-260981 Homo sapiens U2-OS Cell, HeLa Cell
pmid sentence
PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation
Identifier Residue Sequence Organism Cell Line
SIGNOR-260750 Homo sapiens
pmid sentence
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.
Publications: 2 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Innate Immune Response, SARS-CoV STRESS GRANULES
+ Viral_dsRNAup-regulates img/indirect-activation.png EIF2AK2 0.7
Identifier Residue Sequence Organism Cell Line
SIGNOR-260167 Homo sapiens
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Innate Immune Response, Inflammosome Activation, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ DNAJC3down-regulates activity img/direct_inhibition.png binding EIF2AK2 0.626
Identifier Residue Sequence Organism Cell Line
SIGNOR-246207 Homo sapiens HeLa Cell
pmid sentence
The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK
Publications: 1 Organism: Homo Sapiens
+ EIF2AK2down-regulates activity img/direct_inhibition.png phosphorylation EIF2S1 0.721
Identifier Residue Sequence Organism Cell Line
SIGNOR-260168 Homo sapiens
pmid sentence
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)
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ Uridylate-specific endoribonucleasedown-regulates activity img/indirect_inhibition.png EIF2AK2 0.2
Identifier Residue Sequence Organism Cell Line
SIGNOR-260348 Homo sapiens
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, SARS-CoV CYTOKINE STORM, SARS-CoV STRESS GRANULES, SARS-CoV ER STRESS
+ EIF2AK2up-regulates img/indirect-activation.png Immune_response 0.7
Identifier Residue Sequence Organism Cell Line
SIGNOR-260159 Homo sapiens
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Innate Immune Response, Inflammosome Activation, SARS-CoV CYTOKINE STORM, SARS-CoV INFLAMMATORY RESPONSE, SARS-CoV STRESS GRANULES
+ EIF2AK2up-regulates activity img/direct-activation.png binding NLRP1 inflammasome 0.306
Identifier Residue Sequence Organism Cell Line
SIGNOR-263118 Homo sapiens HEK-293 Cell
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:Inflammosome Activation
+ EIF2AK2up-regulates activity img/direct-activation.png binding NLRP3 inflammasome 0.329
Identifier Residue Sequence Organism Cell Line
SIGNOR-263119 Homo sapiens HEK-293 Cell
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Inflammosome Activation, SARS-CoV INFLAMMATORY RESPONSE
+ EIF2AK2up-regulates activity img/direct-activation.png binding NLRC4 inflammasome 0.312
Identifier Residue Sequence Organism Cell Line
SIGNOR-263121 Homo sapiens HEK-293 Cell
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:Inflammosome Activation
+ EIF2AK2up-regulates activity img/direct-activation.png binding AIM2 inflammasome 0.317
Identifier Residue Sequence Organism Cell Line
SIGNOR-263120 Homo sapiens HEK-293 Cell
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:Inflammosome Activation
+ ISGF3 complexup-regulates quantity by expression img/indirect-activation.png transcriptional regulation EIF2AK2 0.49
Identifier Residue Sequence Organism Cell Line
SIGNOR-260158 Homo sapiens
pmid sentence
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.
Publications: 1 Organism: Homo Sapiens
Pathways:COVID-19 Causal Network, Inflammosome Activation, SARS-CoV CYTOKINE STORM, SARS-CoV INFLAMMATORY RESPONSE
+ ADARB1up-regulates activity img/direct-activation.png binding EIF2AK2 0.465
Identifier Residue Sequence Organism Cell Line
SIGNOR-266359 Homo sapiens JURKAT Cell
pmid sentence
Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation.
Publications: 1 Organism: Homo Sapiens
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