Affinage

EIF2AK3

Eukaryotic translation initiation factor 2-alpha kinase 3 · UniProt Q9NZJ5

Length
1116 aa
Mass
125.2 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2AK3 (PERK) is an ER-resident eIF-2α kinase that couples sensing of ER stress to translational and transcriptional reprogramming of the cell. It autophosphorylates on serine/threonine residues and specifically phosphorylates eIF-2α on Ser-51 to inhibit translation, with autophosphorylation and substrate phosphorylation being mechanistically separable functions (PMID:9819435, PMID:10026192). Its N-terminal luminal domain is required for activation during ER stress (PMID:10677345), a step gated by BiP, which switches from its chaperone ATPase cycle into a stress-sensor cycle through interaction with the PERK luminal domain and dissociates from PERK upon accumulation of misfolded proteins (PMID:31695187). Activated PERK signals predominantly through the eIF2α-ATF4 axis to drive diverse outcomes: G1 cell-cycle arrest via loss of cyclin D1 translation (PMID:11035797), replication-fork slowing through Claspin/Chk1 (PMID:27375025), redox and antioxidant homeostasis (PMID:20453876), and a broad mitochondrial program including respiratory supercomplex assembly via ATF4-SCAF1 (PMID:31023583), adaptive phosphatidic-acid remodeling driving protective mitochondrial elongation (PMID:37306086), and a covalent PERK-ERO1α complex at mitochondria-ER contacts that controls Ca2+ flux and bioenergetics (PMID:36586409). In pancreatic beta cells PERK is required during fetal and neonatal development for proliferation, differentiation, and proinsulin proteostasis, the latter mediated through control of ER chaperones BiP and ERp72 and through positive regulation of ERAD rather than synthesis rate (PMID:17141632, PMID:20530744, PMID:29444822). Loss-of-function mutations in EIF2AK3 that abolish or reduce kinase activity cause Wolcott-Rallison syndrome, with residual activity correlating with later-onset neonatal diabetes (PMID:10932183, PMID:15220213). PERK activity is tuned by an array of binding partners and upstream activators, including CNPY2, Thbs1, the viral protein NS4B, and the metabolite TMAO that act as activators (PMID:28869608, PMID:34168130, PMID:31189710, PMID:31543404), and by HSP90, TRIM29, ATAD3A, and Mfn2 that regulate its stability, localization, and local signaling (PMID:30668150, PMID:38664417, PMID:39116259, PMID:34988075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1998 High

    Establishing that PERK is a bona fide eIF-2α kinase defined the molecular activity that anchors all downstream biology.

    Evidence Recombinant kinase produced in E. coli/Sf-9, in vitro kinase assay with Ser-51 specificity, reticulocyte translation assay, and yeast GCN2 complementation

    PMID:9819435

    Open questions at the time
    • Did not address how the kinase is activated in cells
    • No structural basis for substrate recognition
  2. 1999 Medium

    Separating autophosphorylation from substrate phosphorylation and localizing PERK to pancreatic delta cells clarified its catalytic logic and tissue distribution.

    Evidence Lys-614→Ala active-site mutant in Sf-9 cells; immunohistochemical co-localization with somatostatin

    PMID:10026192

    Open questions at the time
    • Delta-cell co-localization did not establish a delta-cell function
    • Mechanism linking autophosphorylation to substrate phosphorylation unresolved
  3. 2000 Medium

    Defining the luminal domain as the ER-stress activation module placed PERK as a transmembrane stress sensor.

    Evidence Deletion of N-terminal luminal sequences abolishing stress-induced autophosphorylation and kinase activity in mammalian cells

    PMID:10677345

    Open questions at the time
    • Did not identify the luminal ligand or sensing mechanism
    • Single domain-deletion approach
  4. 2000 High

    Linking PERK to cyclin D1 loss and G1 arrest, and to Wolcott-Rallison syndrome, connected the kinase to cell-cycle control and human disease.

    Evidence Dominant-negative/overexpression PERK with cyclin D1 immunoblot and flow cytometry; genetic mapping and sequencing of EIF2AK3 in WRS families

    PMID:10932183 PMID:11035797

    Open questions at the time
    • Disease mapping inferred kinase requirement without functional assay of all alleles
    • Cell-cycle mechanism shown in overexpression context
  5. 2004 High

    Functionally testing WRS-associated missense alleles established kinase activity as the disease-relevant output and produced a genotype-phenotype dose relationship.

    Evidence In vitro and in vivo kinase assays of five missense mutants with genotype-phenotype correlation

    PMID:15220213

    Open questions at the time
    • Did not resolve the beta-cell-specific cellular defect
    • Residual-activity threshold for disease onset not defined mechanistically
  6. 2006 High

    Conditional knockout showed PERK acts developmentally in beta cells, dissociating its requirement in fetal/neonatal beta-cell biology from adult glucose homeostasis.

    Evidence Tissue- and cell-specific Perk conditional knockout mice with beta-cell mass, proinsulin trafficking, and secretion analysis

    PMID:17141632

    Open questions at the time
    • Molecular mechanism of trafficking defect not yet defined
    • Why adult beta cells tolerate PERK loss unexplained
  7. 2010 High

    Two studies extended PERK function to ERAD/proteasomal trafficking in beta cells and to antioxidant/ROS control in tumor cells, broadening its proteostatic and redox roles.

    Evidence Perk genetic models with proinsulin trafficking and ERAD assays (Ins2 Akita epistasis); Perk knockout tumor cells with ROS, DNA-damage, and cell-cycle readouts

    PMID:20453876 PMID:20530744

    Open questions at the time
    • Direct PERK substrate(s) in ERAD regulation unidentified
    • How translational control produces antioxidant regeneration not mechanistically dissected
  8. 2013 High

    Development of a selective ATP-competitive inhibitor provided a pharmacological tool validating PERK catalytic output in cells and in vivo.

    Evidence GSK2656157 biochemical assay (IC50 0.9 nM), 300-kinase selectivity panel, cellular phosphorylation, and mouse pharmacodynamics

    PMID:23333938

    Open questions at the time
    • Off-target effects in chronic settings not addressed
    • Does not distinguish translational from non-translational PERK functions
  9. 2016 High

    PERK was shown to enforce a replication checkpoint via Claspin/Chk1 and to be negatively regulated by miR-204, refining its cell-cycle and expression control.

    Evidence Thapsigargin-induced PERK signaling with Claspin/Chk1 depletion and replication assays; miR-204 3′UTR luciferase reporter in human/mouse islets and INS-1 cells

    PMID:27375025 PMID:27384111

    Open questions at the time
    • How PERK promotes Claspin phosphorylation mechanistically unclear
    • Physiological signals controlling miR-204 in vivo not defined
  10. 2017 Medium

    Multiple studies expanded the PERK interactome and downstream effectors, identifying CNPY2 as an activator and CREB3L1, miR-211, and proteasomal cyclin D1/p53 degradation as outputs in stress, circadian, and cancer contexts.

    Evidence Co-IP and CNPY2 knockout mice; PERK genetic manipulation with CREB3L1 invasion assays, miR-211/Bmal1-Clock reporter assays, and proteasome stability assays

    PMID:18418049 PMID:28869608 PMID:29057869 PMID:29230015

    Open questions at the time
    • Whether these branches are cell-type specific or general unresolved
    • Direct biochemical link from PERK to each effector incomplete
  11. 2017 Medium

    Identifying DLK as a neuronal upstream activator of PERK placed the kinase in an injury-responsive integrated stress pathway.

    Evidence Mouse nerve-injury models with DLK/PERK genetic manipulation, ATF4 measurement, and JNK/PERK epistasis

    PMID:28440222

    Open questions at the time
    • Molecular mechanism by which DLK activates PERK not defined
    • Single neuronal injury context
  12. 2018 High

    Mechanistic dissection in beta cells showed PERK controls proinsulin proteostasis through ER chaperones rather than synthesis rate, refuting a synthesis-control model.

    Evidence PERK inhibition in cells/mice with imaging, fractionation, and BiP/ERp72 overexpression-knockdown rescue

    PMID:29444822

    Open questions at the time
    • How PERK signaling modulates ERp72/BiP levels unresolved
    • Whether the same logic applies outside beta cells unknown
  13. 2019 High

    A cluster of studies reconstituted BiP-mediated luminal sensing, identified TMAO as a direct activating ligand, FOXO3 as a transcriptional inducer, JEV NS4B as a dimerization-driving viral activator, and HSP90 as a stabilizing partner, defining how PERK is switched on and maintained.

    Evidence In vitro reconstitution of BiP/PERK ATPase and co-chaperone competition; TMAO binding and PERK-dependent FoxO1 assays; FOXO3 ChIP and triple-KO MEFs; NS4B Co-IP/domain mapping and glycerol-gradient dimerization; HSP90 Co-IP with geldanamycin

    PMID:30668150 PMID:31189710 PMID:31312024 PMID:31543404 PMID:31695187

    Open questions at the time
    • Whether BiP, ligand, and partner inputs are integrated or independent unresolved
    • Structural details of dimerization-driven activation incomplete
  14. 2019 High

    Genome-wide and mitochondrial studies showed PERK selectively represses ER-targeted protein translation and drives respiratory supercomplex assembly, expanding its role beyond global translational shutdown into mitochondrial bioenergetics.

    Evidence Ribo-seq/RNA-seq in WT vs PERK-/- MEFs; PERK ablation/inhibition with supercomplex, SCAF1, and OXPHOS ATP measurements

    PMID:30867432 PMID:31023583

    Open questions at the time
    • How selectivity for ER-targeted transcripts is achieved unclear
    • Direct vs indirect control of SCAF1 by ATF4 not fully resolved
  15. 2021 High

    Thbs1 was identified as a direct PERK activator driving lethal autophagy-mediated cardiac atrophy, extending PERK's ligand-activated biology to the heart.

    Evidence Thbs1-PERK Co-IP, Thbs1 transgenic and cardiac-specific Perk knockout mice, and AAV9-PERK/ATF4 gene transfer

    PMID:34168130

    Open questions at the time
    • Biochemical nature of Thbs1-PERK binding not structurally defined
    • How a secreted matricellular protein engages an ER-luminal sensor unresolved
  16. 2022 High

    Studies in immune cells and mitochondria established PERK-ATF4 metabolic-epigenetic reprogramming in macrophages and MDSC precursors and a covalent PERK-ERO1α complex controlling MERC Ca2+ flux.

    Evidence PERK KO/inhibition in macrophages and HSPCs with metabolomics, PSAT1/ATF4/C-EBPβ dissection, tumor models; ERO1α-PERK Co-IP with C216 mutagenesis and MERC Ca2+ probes

    PMID:35228694 PMID:35266960 PMID:36586409

    Open questions at the time
    • Whether immune and mitochondrial branches share regulatory inputs unknown
    • How covalent ERO1α-PERK linkage forms in vivo not fully characterized
  17. 2022 Medium

    Mfn2 was identified as a MAM-localized partner placing PERK downstream of mitochondrial dynamics control in podocyte injury.

    Evidence Mfn2-PERK Co-IP, Mfn2 siRNA, PERK inhibition, and MAM ultrastructure/mitochondrial function assays in podocytes

    PMID:34988075

    Open questions at the time
    • Whether Mfn2 directly suppresses PERK or via tethering unclear
    • Single cell-type context
  18. 2023 High

    PERK was shown to remodel mitochondrial phosphatidic acid via YME1L-PRELID1 to drive protective mitochondrial elongation, defining a lipid-based mitochondrial adaptation.

    Evidence PERK ablation/activation with PA measurements, YME1L/PRELID1 manipulation, and mitochondrial morphology/fission assays

    PMID:37306086

    Open questions at the time
    • How PERK signaling controls YME1L activity unresolved
    • Whether this axis operates in beta cells or disease unknown
  19. 2024 High

    ATAD3A and TRIM29 were identified as regulators that locally attenuate PERK signaling at MERCs and stabilize PERK by SUMOylation, respectively, revealing spatial and post-translational control of the kinase.

    Evidence ATAD3A-PERK Co-IP, eIF2 competition binding, live-cell translation imaging, and MERC proximity ligation; TRIM29-PERK Co-IP, SUMOylation assays, and TRIM29 knockout viral myocarditis mice

    PMID:38664417 PMID:39116259

    Open questions at the time
    • How ATAD3A competition is dynamically regulated during stress unclear
    • SUMO acceptor sites on PERK not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many luminal activators, cytosolic stabilizers, and spatial regulators are integrated to set PERK signaling thresholds across tissues, and the structural basis of luminal sensing, remains unresolved.
  • No unified structural model of luminal-domain activation
  • Tissue-specific selection among ATF4-dependent output branches undefined
  • Relative contribution of translational vs non-translational PERK functions in vivo unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140299 molecular sensor activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005739 mitochondrion 4 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2
Partners
ATAD3ABIPCNPY2ERO1ΑHSP90MFN2THBS1TRIM29
Complex memberships
PERK-ERO1α covalent complexmitochondria-ER contact sites (MERC/MAM)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PEK (EIF2AK3/PERK) is a new eIF-2α kinase that autophosphorylates on serine and threonine residues and specifically phosphorylates eIF-2α on serine-51 in vitro; addition of recombinant PEK to reticulocyte lysates causes dose-dependent inhibition of translation, and PEK functionally substitutes for yeast GCN2 in a process requiring eIF-2α Ser-51. Recombinant protein produced in E. coli and Sf-9 insect cells; in vitro kinase assay; reticulocyte lysate translation assay; yeast complementation with eIF-2α Ser-51 mutant Molecular and cellular biology High 9819435
1999 A catalytic-dead point mutant of PEK (Lys-614→Ala) abolishes eIF-2α kinase activity but retains autophosphorylation when expressed in Sf-9 cells, demonstrating that autophosphorylation and substrate phosphorylation are mechanistically separable. PEK protein co-localizes with somatostatin in pancreatic delta cells. Site-directed mutagenesis; kinase assay in Sf-9 cells; immunohistochemistry co-localization with somatostatin The Journal of biological chemistry Medium 10026192
2000 The N-terminal luminal domain of PERK/PEK is required for its activation by ER stress; deletion of these N-terminal sequences abolishes elevated PEK autophosphorylation and eIF-2α kinase activity during ER stress in mammalian cells. Deletion mutagenesis of N-terminal luminal sequences; eIF-2α kinase activity assay in mammalian cells under ER stress The Biochemical journal Medium 10677345
2000 PERK activation during the UPR signals loss of cyclin D1 by increasing eIF-2α phosphorylation, thereby blocking cyclin D1 translation and causing G1-phase cell-cycle arrest. A truncated kinase-dead dominant-negative PERK attenuates cyclin D1 loss and cell-cycle arrest without compromising ER chaperone induction. Overexpression of wild-type and dominant-negative PERK; immunoblot for cyclin D1 and p-eIF2α; cell-cycle analysis by flow cytometry Proceedings of the National Academy of Sciences of the United States of America High 11035797
2000 Loss-of-function mutations in EIF2AK3 (truncation removing the catalytic domain, and a missense mutation in the catalytic domain) segregate with Wolcott-Rallison syndrome, establishing that EIF2AK3 kinase activity is required for normal pancreatic beta-cell function and prevention of neonatal diabetes. Genetic mapping; sequencing of EIF2AK3 in affected families; functional inference from catalytic-domain truncation/missense Nature genetics High 10932183
2004 Missense mutations in EIF2AK3 associated with Wolcott-Rallison syndrome produce proteins with complete loss of kinase activity (four mutants) or residual kinase activity (one mutant), as measured in vivo and in vitro; residual activity correlates with later onset of diabetes. In vitro and in vivo kinase activity assays of missense EIF2AK3 mutants; genotype-phenotype correlation Diabetes High 15220213
2006 PERK is specifically required in insulin-secreting beta cells during fetal and early neonatal development for beta-cell proliferation, differentiation, and proinsulin trafficking; PERK expression in adult beta cells is not required to maintain glucose homeostasis, established by tissue-specific conditional knockout. Tissue- and cell-specific Perk conditional knockout mice; developmental analysis of beta-cell mass, proinsulin trafficking, and insulin secretion Cell metabolism High 17141632
2010 Loss of PERK function impairs ER-to-Golgi anterograde trafficking of proinsulin, retrotranslocation from the ER, and proteasomal degradation (ERAD); PERK is a positive regulator of ERAD and proteasomal activity in beta cells. Cell culture and mouse models with Perk impairment or gene-dosage modulation; proinsulin trafficking assays; proteasomal degradation assays; Ins2 Akita mouse epistasis Diabetes High 20530744
2010 PERK deficiency in mammary tumor cells impairs regeneration of intracellular antioxidants, causes accumulation of reactive oxygen species, and triggers oxidative DNA damage and DNA damage checkpoint activation, thereby impeding cell-cycle progression and tumor growth. Perk knockout in tumor cells; ROS measurement; DNA damage markers; cell-cycle analysis; animal mammary carcinoma model Oncogene Medium 20453876
2013 GSK2656157 is an ATP-competitive PERK kinase inhibitor (IC50 0.9 nM) that inhibits PERK autophosphorylation, eIF2α substrate phosphorylation, and downstream ATF4/CHOP induction in cells; oral dosing produces pharmacodynamic inhibition of PERK autophosphorylation in mouse pancreas. Biochemical ATP-competitive kinase assay; cellular phosphorylation assays; kinase selectivity panel (300 kinases); in vivo pharmacodynamic studies in mice Cancer research High 23333938
2016 PERK inhibits DNA replication during ER stress by promoting phosphorylation of the checkpoint adaptor Claspin and activation of Chk1 kinase, leading to replication fork slowing and reduced origin firing, independently of detectable DNA damage; Claspin depletion or Chk1 inhibition abolishes PERK-dependent DNA synthesis inhibition. PERK-dependent thapsigargin treatment; DNA synthesis assays; Claspin and Chk1 depletion/inhibition; replication origin firing analysis Oncogene High 27375025
2017 PERK promotes degradation of cyclin D1 and p53 via the 26S proteasome during ER stress, representing a non-translational function of PERK in regulating protein stability. Overexpression/loss-of-function of PERK during ER stress; proteasome inhibitor experiments; protein stability assays Cell cycle (Georgetown, Tex.) Medium 18418049
2017 PERK induces expression of miR-211 upon UPR activation; miR-211 directly suppresses Bmal1 and Clock to produce a 10-hour phase shift in circadian oscillations, and repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation. miRNA profiling; miR-211 target validation; luciferase reporter assays; PERK genetic manipulation; protein synthesis assays Nature cell biology Medium 29230015
2017 CNPY2 (canopy homolog 2) is released from GRP78 upon ER stress and engages PERK to induce CHOP expression, initiating the UPR; CNPY2 deletion blocks the PERK-CHOP pathway in vivo. Co-immunoprecipitation of CNPY2 with PERK; CNPY2 knockout mice; CHOP pathway reporter assays; liver damage model Nature structural & molecular biology High 28869608
2017 PERK drives cancer invasion and metastasis through the transcription factor CREB3L1, which acts downstream of PERK specifically in mesenchymal triple-negative breast cancer cells; inhibition of CREB3L1 suppresses PERK-dependent invasion. PERK and CREB3L1 genetic manipulation; invasion and metastasis assays in vitro and in vivo; epistasis placing CREB3L1 downstream of PERK Nature communications Medium 29057869
2017 DLK (Dual Leucine Zipper Kinase) activates PERK signaling in neurons in response to nerve injury and neurotrophin deprivation, leading to ATF4 upregulation via the ISR; disruption of PERK signaling delays neurodegeneration without reducing JNK signaling, placing PERK downstream of DLK in a neuronal stress pathway. Mouse nerve injury models; DLK and PERK genetic manipulation; ATF4 measurement; JNK and PERK pathway epistasis eLife Medium 28440222
2018 PERK regulates proinsulin proteostasis not by controlling synthesis rates (global protein and proinsulin synthesis are both down-regulated in PERK-inhibited cells) but by modulating ER chaperones BiP and ERp72; ERp72 overexpression rescues proinsulin aggregation whereas BiP manipulation promotes it. PERK inhibition in cell culture and mice; high-resolution imaging; protein fractionation; immunological assays; BiP and ERp72 overexpression/knockdown The Journal of biological chemistry High 29444822
2019 BiP interaction with the luminal domains of PERK (and IRE1) switches BiP from its chaperone ATPase cycle into an ER stress sensor cycle by preventing co-chaperone binding and loss of ATPase stimulation; misfolded protein-dependent dissociation of BiP from PERK/IRE1 is primed by ATP but not ADP. Reconstitution of human UPR components in vitro; biochemical co-chaperone binding assays; ATPase stimulation assays; nucleotide (ATP vs ADP) dependence experiments Nature structural & molecular biology High 31695187
2019 TMAO (trimethylamine N-oxide) directly binds to PERK at physiologically relevant concentrations and selectively activates the PERK branch of the UPR, inducing FoxO1 in a PERK-dependent manner; interventions reducing TMAO reduce PERK activation and FoxO1 levels in liver. Direct TMAO-PERK binding assay; selective UPR branch activation assays; PERK-dependent FoxO1 induction; gut microbiota manipulation and FMO3 inhibition experiments in vivo Cell metabolism High 31543404
2019 PERK activation during ER stress and glucose deprivation stimulates formation of respiratory chain supercomplexes (SCs) through the PERK-eIF2α-ATF4 axis, which increases SCAF1 (COX7A2L) expression; PERK ablation suppresses SC levels and oxidative phosphorylation-dependent ATP production. Genetic ablation and pharmacological inhibition of PERK; measurement of SC levels; SCAF1 expression; OXPHOS ATP production; PERK activation in mitochondrial disease patient cells Molecular cell High 31023583
2019 PERK-dependent translational inhibition extends beyond global translation to specifically repress ER-targeted proteins (transmembrane, glycoproteins, disulfide-bond-containing) via ribosome footprint profiling; PERK also attenuates expression of a subset of XBP1-ATF6 UPR targets, demonstrating cross-talk between UPR branches. Ribosome footprint profiling (Ribo-seq) in WT vs PERK-/- mouse embryonic fibroblasts; RNA-seq; ER stress time-course experiments Scientific reports Medium 30867432
2021 Thrombospondin-1 (Thbs1) directly binds and activates PERK, inducing its downstream transcription factor ATF4 and causing autophagy-mediated lethal cardiac atrophy; genetic deletion of PERK in Thbs1 transgenic mice blunts ATF4 induction, autophagy, and cardiac atrophy. Co-immunoprecipitation of Thbs1 and PERK; Thbs1 transgenic mice; Perk cardiac-specific knockout; ATF4 and autophagy marker measurement; AAV9 gene transfer of PERK and ATF4 Nature communications High 34168130
2022 The oxidoreductase ERO1α covalently interacts with PERK upon ER stress (tunicamycin treatment), requiring the C-terminal active site of ERO1α and cysteine 216 of PERK; the PERK-ERO1α complex promotes oxidization of mitochondria-ER contact (MERC) proteins, controls mitochondrial dynamics, and improves ER-mitochondria Ca2+ flux to maintain bioenergetics. Co-immunoprecipitation; cysteine mutagenesis (C216 of PERK); proteinaceous Ca2+ probes at MERC; mitochondrial dynamics imaging; bioenergetic assays Cell reports High 36586409
2022 PERK mediates immunosuppressive M2 macrophage activation and proliferation downstream of IL-4 and tumor microenvironment signals, acting through the PERK-ATF4 axis to upregulate PSAT1 (phosphoserine aminotransferase 1) and serine biosynthesis; increased serine leads to enhanced α-ketoglutarate production required for JMJD3-dependent epigenetic modification. PERK knockout/inhibition in macrophages; metabolomics; ATF4 and PSAT1 genetic manipulation; α-ketoglutarate and JMJD3 assays; in vivo tumor models Nature immunology High 35228694
2022 PERK in hematopoietic stem/progenitor cells (HSPCs) in the spleen reprograms HSPCs into committed MDSC precursors via PERK-ATF4-C/EBPβ signaling; pharmacological or genetic PERK inhibition in HSPCs prevents myeloid descendants from becoming MDSCs. Genetic and pharmacological PERK inhibition in murine and human HSPCs; spleen-targeted PERK antagonist delivery; tumor models; MDSC functional assays The Journal of experimental medicine Medium 35266960
2023 PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) during acute ER stress, requiring YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1; accumulated outer-mitochondrial-membrane PA inhibits mitochondrial fission and induces protective mitochondrial elongation. PERK genetic ablation and activation; PA lipid measurements; YME1L and PRELID1 genetic manipulation; mitochondrial morphology imaging; fission assays The EMBO journal High 37306086
2024 ATAD3A (mitochondrial ATPase AAA domain-containing protein 3A) interacts with PERK and competes for binding with PERK's target eIF2, forming mitochondria-ER contact sites; during ER stress PERK-ATAD3A interactions increase, attenuating local PERK signaling at mitochondria and protecting active translation there from ER stress-induced repression. Live-cell imaging of reporter mRNA translation; Co-immunoprecipitation of PERK-ATAD3A; competition binding assay with eIF2; ATAD3A knockdown; PERK-ATAD3A proximity ligation at mitochondria-ER contacts Science (New York, N.Y.) High 39116259
2024 TRIM29 interacts with PERK and promotes SUMOylation of PERK to maintain its protein stability, thereby sustaining PERK-mediated signaling pathways in cardiomyocytes during viral infection; TRIM29 loss reduces PERK stability and PERK-mediated ER stress responses. Co-immunoprecipitation of TRIM29 and PERK; SUMOylation assays; TRIM29 knockout mice; viral myocarditis model; PERK stability assays Nature communications Medium 38664417
2016 miR-204 directly targets the 3′UTR of PERK mRNA and reduces PERK protein expression and downstream ATF4/CHOP signaling in beta cells; miR-204-mediated PERK inhibition exacerbates ER stress-induced beta-cell apoptosis. 3′UTR luciferase reporter assay; miR-204 overexpression in primary human islets, mouse islets, and INS-1 cells; immunoblot for PERK and downstream targets; cell death assays Molecular endocrinology (Baltimore, Md.) Medium 27384111
2019 FOXO3 directly binds the PERK promoter and transcriptionally activates PERK expression, as confirmed by ChIP, siRNA knockdown, overexpression assays, and Foxo1/3/4-/- MEFs; PERK is thus a direct transcriptional downstream target of FOXO3. ChIP; siRNA knockdown; FOXO3 overexpression; Foxo1/3/4 triple-knockout MEFs; RT-qPCR and immunoblot Oncogene Medium 31312024
2019 JEV non-structural protein NS4B binds PERK via its LIG-FHA and LIG-WD40 domains (both required), inducing PERK dimerization, which is the mechanistic basis of JEV-induced PERK activation leading to the PERK-ATF4-CHOP apoptosis pathway. Co-immunoprecipitation of NS4B with PERK; glycerol gradient centrifugation for PERK dimerization; domain-deletion mutagenesis of NS4B; PERK inhibitor experiments in vitro and in vivo Journal of virology Medium 31189710
2019 PTH induces ER stress in osteoblasts through the PERK-eIF2α-ATF4 signaling pathway; HSP90 interacts with PERK and maintains PERK protein stabilization early during PTH-induced ER stress; HSP90 inhibition decreases PERK protein expression and inhibits osteoblast differentiation and proliferation upon PTH treatment. PERK/ATF4 siRNA and pharmacological inhibitors; co-immunoprecipitation of HSP90 with PERK; geldanamycin (HSP90 inhibitor) treatment; osteoblast differentiation and proliferation assays American journal of physiology. Endocrinology and metabolism Medium 30668150
2022 Mfn2 physically interacts with PERK at mitochondria-associated ER membranes (MAMs); high glucose promotes a decrease in the Mfn2-PERK interaction; Mfn2 silencing activates the PERK pathway and increases podocyte apoptosis, while PERK inhibition protects mitochondrial function without affecting Mfn2 expression, placing PERK downstream of Mfn2 at MAMs. Co-immunoprecipitation of Mfn2 and PERK; Mfn2 siRNA knockdown; PERK inhibitor treatment; MAM ultrastructure analysis; mitochondrial function assays in podocytes Frontiers in cell and developmental biology Medium 34988075

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 672 9819435
2000 EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature genetics 655 10932183
2013 Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer research 393 23333938
2000 PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proceedings of the National Academy of Sciences of the United States of America 386 11035797
2019 UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nature structural & molecular biology 333 31695187
2019 Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. Cell metabolism 332 31543404
2019 ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis. Molecular cell 284 31023583
2009 Divergent effects of PERK and IRE1 signaling on cell viability. PloS one 267 19137072
2010 PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 253 20453876
2006 PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell metabolism 230 17141632
2022 PERK is a critical metabolic hub for immunosuppressive function in macrophages. Nature immunology 201 35228694
2017 PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy. Molecular cancer 158 28499449
2004 Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 153 15220213
2021 Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. Nature communications 137 34168130
2019 ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling. Cell communication and signaling : CCS 136 31060556
2018 The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway. The FEBS journal 134 29476642
2000 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. The Biochemical journal 133 10677345
2014 Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 130 24589849
2010 PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 121 20530744
2017 Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1. Nature communications 117 29057869
2006 Divergent roles of IRE1alpha and PERK in the unfolded protein response. Current molecular medicine 108 16472110
2017 PERK activation mitigates tau pathology in vitro and in vivo. EMBO molecular medicine 102 28148553
2012 Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PloS one 102 22253692
2017 A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nature cell biology 93 29230015
2021 Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway. Frontiers in cell and developmental biology 92 34988075
2024 Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice. Nature communications 89 38664417
2020 PERK controls bone homeostasis through the regulation of osteoclast differentiation and function. Cell death & disease 88 33051453
2017 Recent insights into PERK-dependent signaling from the stressed endoplasmic reticulum. F1000Research 85 29152224
2022 The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria. Cell reports 82 36586409
2016 PERK-opathies: An Endoplasmic Reticulum Stress Mechanism Underlying Neurodegeneration. Current Alzheimer research 81 26679859
2008 PERK and PKR: old kinases learn new tricks. Cell cycle (Georgetown, Tex.) 78 18418049
2016 PERK Integrates Oncogenic Signaling and Cell Survival During Cancer Development. Journal of cellular physiology 74 26864318
2011 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity. PLoS genetics 70 22125500
2020 The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases. International journal of molecular sciences 67 32204380
2019 Radiation induces EIF2AK3/PERK and ERN1/IRE1 mediated pro-survival autophagy. Autophagy 67 30773986
2024 IRE1 signaling increases PERK expression during chronic ER stress. Cell death & disease 65 38637497
2019 Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway. Journal of virology 65 31189710
2023 Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer. Redox biology 63 37536085
2017 Dual leucine zipper kinase-dependent PERK activation contributes to neuronal degeneration following insult. eLife 61 28440222
2021 PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate? Biomolecules 60 33652720
2019 The PERK-EIF2α-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH. American journal of physiology. Endocrinology and metabolism 60 30668150
2010 PERK in beta cell biology and insulin biogenesis. Trends in endocrinology and metabolism: TEM 57 20850340
2022 Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes. Nature communications 56 36216837
2017 Fine-tuning PERK signaling for neuroprotection. Journal of neurochemistry 56 28643372
2018 PERK regulates skeletal muscle mass and contractile function in adult mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 55 30204503
2017 CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response. Nature structural & molecular biology 55 28869608
2004 Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta paediatrica (Oslo, Norway : 1992) 55 15384883
1999 Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. The Journal of biological chemistry 55 10026192
2015 Tumor progression and the different faces of the PERK kinase. Oncogene 53 26028033
2013 PERK-ing up autophagy during MYC-induced tumorigenesis. Autophagy 53 23328692
2020 A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models. Scientific reports 52 32327686
2019 Widespread PERK-dependent repression of ER targets in response to ER stress. Scientific reports 51 30867432
2015 Expression of pERK and VEGFR-2 in advanced hepatocellular carcinoma and resistance to sorafenib treatment. Liver international : official journal of the International Association for the Study of the Liver 51 25559745
2016 miR-204 Targets PERK and Regulates UPR Signaling and β-Cell Apoptosis. Molecular endocrinology (Baltimore, Md.) 50 27384111
2012 An exploratory study on STX6, MOBP, MAPT, and EIF2AK3 and late-onset Alzheimer's disease. Neurobiology of aging 49 23116876
2019 Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Scientific reports 48 31239473
2020 Mitoxantrone triggers immunogenic prostate cancer cell death via p53-dependent PERK expression. Cellular oncology (Dordrecht, Netherlands) 47 32710433
2023 PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid. The EMBO journal 45 37306086
2024 PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress. Science (New York, N.Y.) 38 39116259
2018 The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones. The Journal of biological chemistry 38 29444822
2016 PERK inhibits DNA replication during the Unfolded Protein Response via Claspin and Chk1. Oncogene 38 27375025
2010 Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Pediatric diabetes 38 20202148
2019 Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells. Oncogene 37 31312024
2020 Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention. Progress in neurobiology 36 32795489
2019 Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death. International journal of molecular sciences 36 31491992
2022 PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen. The Journal of experimental medicine 35 35266960
2021 PERK signaling pathway in bone metabolism: Friend or foe? Cell proliferation 35 33615575
2012 ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics. World journal of surgical oncology 34 22376079
2017 Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis. Scientific reports 33 29213084
2019 Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival. Cancer research 32 31672843
2020 Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity. Cancers 28 33028016
2020 PERK Inhibition Mitigates Restenosis and Thrombosis: A Potential Low-Thrombogenic Antirestenotic Paradigm. JACC. Basic to translational science 27 32215348
2019 Liraglutide Increases VEGF Expression via CNPY2-PERK Pathway Induced by Hypoxia/Reoxygenation Injury. Frontiers in pharmacology 27 31396081
2017 PERK and XBP1 differentially regulate CXCL10 and CCL2 production. Experimental eye research 27 28065589
2016 Protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015). Expert opinion on therapeutic patents 27 27646439
2020 The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells. Cancer letters 26 32679165
2018 Neurite atrophy and apoptosis mediated by PERK signaling after accumulation of GM2-ganglioside. Biochimica et biophysica acta. Molecular cell research 26 30389374
2016 PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility. PloS one 26 27627766
2022 PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells. Scientific reports 25 35922637
2019 Ginseng metabolite Protopanaxadiol induces Sestrin2 expression and AMPK activation through GCN2 and PERK. Cell death & disease 25 30952841
2020 Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK. Current biology : CB 24 32169212
2020 Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons. EBioMedicine 24 33341442
2016 Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis. Cell stress & chaperones 24 27761878
2023 PERK inhibitor, GSK2606414, ameliorates neuropathological damage, memory and motor functional impairments in cerebral ischemia via PERK/p-eIF2ɑ/ATF4/CHOP signaling. Metabolic brain disease 23 36847967
2023 PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy. The Journal of cell biology 23 37022709
2023 PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 37166058
2021 The Role of PERK in Understanding Development of Neurodegenerative Diseases. International journal of molecular sciences 21 34360909
2023 Toosendanin induced hepatotoxicity via triggering PERK-eIF2α-ATF4 mediated ferroptosis. Toxicology letters 20 36801351
2018 Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK). Reviews in the neurosciences 20 29303785
2016 Perk Ablation Ameliorates Myelination in S63del-Charcot-Marie-Tooth 1B Neuropathy. ASN neuro 20 27095827
2014 Perk gene dosage regulates glucose homeostasis by modulating pancreatic β-cell functions. PloS one 20 24915520
2021 PERK mediates oxidative stress and adipogenesis in Graves' orbitopathy pathogenesis. Journal of molecular endocrinology 19 33870911
2020 Reciprocal regulation between GCN2 (eIF2AK4) and PERK (eIF2AK3) through the JNK-FOXO3 axis to modulate cancer drug resistance and clonal survival. Molecular and cellular endocrinology 19 32615282
2016 Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum. Biological chemistry 19 26872313
2020 PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma. Oncogenesis 18 32054826
2022 Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. The Journal of biological chemistry 17 36563857
2008 PERK-dependent regulation of HSP70 expression and the regulation of autophagy. Autophagy 17 18216498
2022 CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress. Cell and tissue research 16 36525128
2021 IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity. Allergy 16 34314538
2021 PERK in POMC neurons connects celastrol with metabolism. JCI insight 16 34549728

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