EIF2AK3 encodes PERK, an endoplasmic-reticulum-resident type I transmembrane stress-sensor kinase. Its luminal domain responds to misfolded proteins and ER stress activates the cytoplasmic kinase domain. PERK phosphorylates EIF2S1/eIF2alpha to attenuate translation initiation and promote the PERK arm of the unfolded protein response and integrated stress response. PERK also autophosphorylates on tyrosine as part of its activation and contributes to stress-dependent cell survival, differentiation, and apoptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase term rather than a generic kinase annotation. Reason: Use the child term that captures PERK's established substrate specificity. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0004672 protein kinase activity | TAS PMID:10026192 Characterization of a mutant pancreatic eIF-2alpha kinase, P... | MODIFY | Summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase term rather than a generic kinase annotation. Reason: Use the child term that captures PERK's established substrate specificity. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0004672 protein kinase activity | IDA PMID:9819435 Identification and characterization of pancreatic eukaryotic... | MODIFY | Summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase term rather than a generic kinase annotation. Reason: Use the child term that captures PERK's established substrate specificity. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0004674 protein serine/threonine kinase activity | ISS GO_REF:0000024 | MODIFY | Summary: PERK is a serine/threonine kinase, but the more specific eIF2alpha kinase term is the best curated representation of its catalytic activity. Reason: GO:0004694 captures the specific kinase activity directly tied to PERK biology. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: PERK is a serine/threonine kinase, but the more specific eIF2alpha kinase term is the best curated representation of its catalytic activity. Reason: GO:0004694 captures the specific kinase activity directly tied to PERK biology. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. file:human/EIF2AK3/EIF2AK3-deep-research-falcon.md PERK's primary enzymatic function is to phosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha; gene EIF2S1) at Ser51. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:10026192 Characterization of a mutant pancreatic eIF-2alpha kinase, P... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:10026192 a point mutation that replaced the conserved Lys-614 with an alanine completely abolished the eIF-2alpha kinase activity, whereas the mutant PEK was still autophosphorylated when expressed in Sf-9 cells. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:10677345 In mammalian cells subjected to ER stress, we found that elevated eIF-2alpha phosphorylation was coincident with increased PEK autophosphorylation and eIF-2alpha kinase activity. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:11907036 Phosphorylation of eukaryotic initiation factor-2 (eIF2) by pancreatic eIF2 kinase (PEK), induces a program of translational expression in response to accumulation of malfolded protein in the endoplasmic reticulum (ER). |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IMP PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:12086964 The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha). |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IMP PMID:25329545 p58IPK is an inhibitor of the eIF2Ξ± kinase GCN2 and its loca... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:25329545 p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2Ξ± kinases PKR (dsRNA-dependent protein kinase/eIF2Ξ± kinase 2) and PERK and hence prevent or delay eIF2Ξ± phosphorylation. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:25925385 Crystal structures reveal transient PERK luminal domain tetr... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:25925385 Additionally, PERK mutants reduce tetramer formation in vitro and reduce PERK and eIf2a phosphorylation in cells. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:31023583 The PERK-eIF2Ξ±-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. |
| GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity | IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo... | ACCEPT | Summary: This is the core catalytic activity of PERK and is directly supported by biochemical and cell-based studies of eIF2alpha phosphorylation during ER stress. Reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase. Supporting Evidence: PMID:39116259 The mitochondrial protein ATPase family AAA domain-containing protein 3A (ATAD3A) interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and mediated this effect on localized translation by competing for binding with PERK's target, eukaryotic initiation factor 2 (eIF2). |
| GO:0004713 protein tyrosine kinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: PERK has experimentally demonstrated tyrosine autophosphorylation activity. Reason: PMID:17998206 demonstrates PERK tyrosine autophosphorylation in vitro and in cells and classifies PERK as a dual-specificity kinase. Its canonical substrate eIF2alpha is phosphorylated on serine, but that does not negate the tyrosine-kinase activity supporting these conserved transfers. The verified GO definition is catalysis of ATP plus a protein tyrosine to ADP plus protein tyrosine phosphate; it does not require a different protein substrate or trans phosphorylation. PERK itself is the protein substrate in autophosphorylation. Dual specificity does not negate either constituent catalytic activity. Supporting Evidence: PMID:17998206 PERK also possesses tyrosine kinase activity. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: PERK has experimentally demonstrated tyrosine autophosphorylation activity. Reason: PMID:17998206 demonstrates PERK tyrosine autophosphorylation in vitro and in cells and classifies PERK as a dual-specificity kinase. Its canonical substrate eIF2alpha is phosphorylated on serine, but that does not negate the tyrosine-kinase activity supporting these conserved transfers. The verified GO definition is catalysis of ATP plus a protein tyrosine to ADP plus protein tyrosine phosphate; it does not require a different protein substrate or trans phosphorylation. PERK itself is the protein substrate in autophosphorylation. Dual specificity does not negate either constituent catalytic activity. Supporting Evidence: PMID:17998206 PERK also possesses tyrosine kinase activity. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA GO_REF:0000003 | REMOVE | Summary: Wild-type PERK is a single-pass ER transmembrane kinase, so non-membrane-spanning protein tyrosine kinase activity is incorrect. Reason: This term conflicts with the architecture and known activity of EIF2AK3. |
| GO:0005515 protein binding | IPI PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | REMOVE | Summary: The reported interaction is retained as biological evidence, but generic protein binding is uninformative. Reason: Generic protein binding does not identify the catalytic or regulatory function of PERK. Removal follows the project policy for this term and does not dispute the reported physical interaction. A specific replacement requires partner-specific functional evidence. |
| GO:0005515 protein binding | IPI PMID:25393282 TBL2 is a novel PERK-binding protein that modulates stress-s... | REMOVE | Summary: The reported interaction is retained as biological evidence, but generic protein binding is uninformative. Reason: Generic protein binding does not identify the catalytic or regulatory function of PERK. Removal follows the project policy for this term and does not dispute the reported physical interaction. A specific replacement requires partner-specific functional evidence. |
| GO:0005515 protein binding | IPI PMID:26268696 TMEM33: a new stress-inducible endoplasmic reticulum transme... | REMOVE | Summary: The reported interaction is retained as biological evidence, but generic protein binding is uninformative. Reason: Generic protein binding does not identify the catalytic or regulatory function of PERK. Removal follows the project policy for this term and does not dispute the reported physical interaction. A specific replacement requires partner-specific functional evidence. |
| GO:0005515 protein binding | IPI PMID:27238082 Compounds Triggering ER Stress Exert Anti-Melanoma Effects a... | REMOVE | Summary: The reported interaction is retained as biological evidence, but generic protein binding is uninformative. Reason: Generic protein binding does not identify the catalytic or regulatory function of PERK. Removal follows the project policy for this term and does not dispute the reported physical interaction. A specific replacement requires partner-specific functional evidence. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is intrinsic to PERK kinase catalysis. Reason: The conserved kinase activity consumes ATP. This broad molecular function is correct; being less informative than the kinase term does not make it an over-annotation. Supporting Evidence: UniProt:Q9NZJ5 Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + |
| GO:0019899 enzyme binding | IPI PMID:23103912 PARP16 is a tail-anchored endoplasmic reticulum protein requ... | MARK AS OVER ANNOTATED | Summary: Partner-specific regulatory enzyme interactions exist, but the broad enzyme binding term is not the best way to capture PERK biology. Reason: Specific process or partner-focused annotations are more informative than generic enzyme binding. |
| GO:0019903 protein phosphatase binding | IPI PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | KEEP AS NON CORE | Summary: Binding to phosphatase regulators such as PTP1B is mechanistically relevant for ER-stress tuning, but it is contextual rather than the core evolved role of PERK. Reason: Retain as specific non-core regulatory context. |
| GO:0042802 identical protein binding | IPI PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | KEEP AS NON CORE | Summary: PERK oligomerization is mechanistically real, but identical protein binding is an enabling context rather than a standalone core function. Reason: Homomerization supports activation without defining PERK's main molecular output. |
| GO:0045182 translation regulator activity | ISS GO_REF:0000024 | MODIFY | Summary: PERK does regulate translation, but the best molecular function curation is its specific eIF2alpha kinase activity rather than a generic translation regulator term. Reason: Replace the broad activity term with the specific catalytic activity. Proposed replacements: eukaryotic translation initiation factor 2alpha kinase activity |
| GO:0051787 misfolded protein binding | IDA PMID:27917829 The ER stress sensor PERK luminal domain functions as a mole... | ACCEPT | Summary: Direct misfolded-protein recognition by the luminal domain is supported experimentally and fits PERK's role as an ER stress sensor. Reason: This term captures an experimentally supported sensing mechanism upstream of PERK activation. Supporting Evidence: PMID:27917829 the PERK luminal domain can recognize and selectively interact with misfolded proteins but not native proteins. |
| GO:0051879 Hsp90 protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PERK interacts with the Hsp90-family chaperone GRP94/HSP90B1. Reason: The Ensembl transfer is corroborated by the human PERK literature: PMID:11907036 reports association with GRP94, an Hsp90-family chaperone, and release on ER stress. The prior assertion that this was IEA-only and unsupported overlooked that evidence. Supporting Evidence: PMID:11907036 PEK associates with ER chaperones GRP78 |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific eIF2alpha kinase annotation. Reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0106310 protein serine kinase activity | EXP PMID:10026192 Characterization of a mutant pancreatic eIF-2alpha kinase, P... | ACCEPT | Summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific eIF2alpha kinase annotation. Reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0106310 protein serine kinase activity | EXP PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ... | ACCEPT | Summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific eIF2alpha kinase annotation. Reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0001501 skeletal system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Skeletal development phenotypes in Wolcott-Rallison syndrome reflect physiological dependence on PERK signaling, but developmental outcomes are not the core biochemical role of EIF2AK3. Reason: Retain as downstream organismal phenotype context, not core function. Supporting Evidence: PMID:12086964 Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans |
| GO:0001503 ossification | IMP PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | KEEP AS NON CORE | Summary: Ossification defects are part of the Wolcott-Rallison phenotype and reflect tissue dependence on PERK signaling rather than PERK's core molecular job. Reason: Keep as a non-core physiological consequence. Supporting Evidence: PMID:12086964 Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans |
| GO:0001525 angiogenesis | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | KEEP AS NON CORE | Summary: Tumor angiogenesis downstream of PERK-ATF4 signaling is supported in specialized stress contexts but is not a constitutive core role of EIF2AK3. Reason: Retain as contextual stress-pathway output. Supporting Evidence: PMID:22915762 Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. |
| GO:0002063 chondrocyte development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Chondrocyte developmental phenotypes fit the broader Wolcott-Rallison developmental syndrome, but they are not the core evolved molecular role of PERK. Reason: Keep developmental consequences separate from core ISR/UPR biology. Supporting Evidence: PMID:12086964 Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans |
| GO:0006446 regulation of translational initiation | IBA GO_REF:0000033 | ACCEPT | Summary: PERK phosphorylation of eIF2alpha regulates translation initiation. Reason: This IBA describes the conserved eIF2-kinase role at an appropriate broader level. The stress-specific child terms add context but do not replace or contradict the ancestral translation-regulation assertion. Supporting Evidence: UniProt:Q9NZJ5 EIF2S1/eIF-2-alpha phosphorylation in response to stress converts CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to CC a global attenuation of cap-dependent translation |
| GO:0006983 ER overload response | IDA PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ... | UNDECIDED | Summary: The experimental annotation requires full-text adjudication. Reason: The cached original publication is abstract-only. Its emphasis on a different stress response or transcriptional output is insufficient to establish that the annotated assay was absent. The previous confident removal is withdrawn pending recovery of the full text and verification of the specific annotated process. |
| GO:0006983 ER overload response | IDA PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | UNDECIDED | Summary: The experimental annotation requires full-text adjudication. Reason: The cached original publication is abstract-only. Its emphasis on a different stress response or transcriptional output is insufficient to establish that the annotated assay was absent. The previous confident removal is withdrawn pending recovery of the full text and verification of the specific annotated process. |
| GO:0007029 endoplasmic reticulum organization | ISS GO_REF:0000024 | UNDECIDED | Summary: PERK can influence ER architecture and ER-mitochondria contacts, but current support is not sufficient to treat ER organization as a clean reviewed annotation for human EIF2AK3. Reason: More direct evidence would be needed to retain or remove confidently. |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | KEEP AS NON CORE | Summary: PERK can promote VEGF production in tumor stress settings, but that is a contextual downstream output rather than a core homeostatic role. Reason: Retain as stress-contextual non-core biology. Supporting Evidence: PMID:22915762 Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. |
| GO:0010628 positive regulation of gene expression | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | MARK AS OVER ANNOTATED | Summary: PERK signaling influences transcriptional programs via ATF4, NRF2, and CHOP, but this broad term obscures the specific stress pathways involved. Reason: Prefer pathway-specific process terms over a generic gene-expression label. |
| GO:0017148 negative regulation of translation | IBA GO_REF:0000033 | ACCEPT | Summary: PERK phosphorylation of eIF2alpha regulates translation initiation. Reason: This IBA describes the conserved eIF2-kinase role at an appropriate broader level. The stress-specific child terms add context but do not replace or contradict the ancestral translation-regulation assertion. Supporting Evidence: UniProt:Q9NZJ5 EIF2S1/eIF-2-alpha phosphorylation in response to stress converts CC EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to CC a global attenuation of cap-dependent translation |
| GO:0017148 negative regulation of translation | IEA GO_REF:0000117 | ACCEPT | Summary: PERK attenuates translation by phosphorylating eIF2alpha. Reason: This conserved translation-regulation function is supported by the specific stress-response annotations. The broader term remains correct and does not imply activity outside the documented contexts. |
| GO:0017148 negative regulation of translation | TAS PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | ACCEPT | Summary: PERK attenuates translation by phosphorylating eIF2alpha. Reason: This conserved translation-regulation function is supported by the specific stress-response annotations. The broader term remains correct and does not imply activity outside the documented contexts. |
| GO:0019722 calcium-mediated signaling | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Calcium perturbation can trigger PERK, but EIF2AK3 is not best captured as a general calcium-mediated signaling gene. Reason: This is too broad relative to the direct ER-stress sensing role. |
| GO:0030282 bone mineralization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Bone mineralization defects are well aligned with Wolcott-Rallison syndrome, but they represent organismal consequences of PERK loss rather than its core molecular function. Reason: Retain as non-core developmental phenotype context. Supporting Evidence: PMID:12086964 Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ... | ACCEPT | Summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response is well supported. Reason: This process term accurately captures a central branch of EIF2AK3 biology. Supporting Evidence: PMID:10677345 PEK, also referred to as RNA-dependent protein kinase (PKR)-like endoplasmic reticulum (ER) kinase (PERK) is a transmembrane protein implicated in translational control in response to stresses that impair protein folding in the ER. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | ACCEPT | Summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response is well supported. Reason: This process term accurately captures a central branch of EIF2AK3 biology. Supporting Evidence: PMID:11907036 In the absence of stress, PEK associates with ER chaperones GRP78 (BiP) and GRP94, and this binding is released in response to ER stress. |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS PMID:19816510 Essential role of the unfolded protein response regulator GR... | ACCEPT | Summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response is well supported. Reason: This process term accurately captures a central branch of EIF2AK3 biology. Supporting Evidence: PMID:19816510 GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and GADD34, feedback suppression of eIF2alpha phosphorylation and apoptotic cell death. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | ACCEPT | Summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response is well supported. Reason: This process term accurately captures a central branch of EIF2AK3 biology. Supporting Evidence: PMID:22169477 Suppression of CSE decreased H(2)S production and decreased the phosphorylation of tyrosine-619 in PERK [protein kinase-like endoplasmic reticulum (ER) kinase], thus reducing its activation in response to ER stress. |
| GO:0031018 endocrine pancreas development | IMP PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | KEEP AS NON CORE | Summary: Pancreatic developmental and islet phenotypes in Wolcott-Rallison syndrome are real, but they are downstream tissue consequences rather than core PERK molecular function. Reason: Keep tissue-development outcomes separate from core ISR/UPR roles. Supporting Evidence: PMID:12086964 Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans |
| GO:0031642 negative regulation of myelination | ISS GO_REF:0000024 | UNDECIDED | Summary: The transferred process requires donor-specific evidence review. Reason: The earlier rationale rejected this annotation because it was peripheral to canonical ER-stress sensing or because direct support was not identified. Neither argument establishes a false transfer. The underlying ortholog or rule evidence must be recovered to distinguish a supported contextual role from an erroneous propagation. |
| GO:0032055 negative regulation of translation in response to stress | IEA GO_REF:0000107 | ACCEPT | Summary: PERK-dependent eIF2alpha phosphorylation directly attenuates translation under stress; this matches the central ISR and proteostasis role of EIF2AK3. Reason: This is a core PN-aligned process for PERK. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0032057 negative regulation of translational initiation in response to stress | TAS PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ... | ACCEPT | Summary: PERK directly suppresses translation initiation during stress through eIF2alpha phosphorylation. Reason: This is the mechanistically precise form of PERK-mediated translation attenuation. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0032057 negative regulation of translational initiation in response to stress | TAS PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | ACCEPT | Summary: PERK directly suppresses translation initiation during stress through eIF2alpha phosphorylation. Reason: This is the mechanistically precise form of PERK-mediated translation attenuation. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0034198 cellular response to amino acid starvation | IEA GO_REF:0000117 | UNDECIDED | Summary: The transferred process requires donor-specific evidence review. Reason: The earlier rationale rejected this annotation because it was peripheral to canonical ER-stress sensing or because direct support was not identified. Neither argument establishes a false transfer. The underlying ortholog or rule evidence must be recovered to distinguish a supported contextual role from an erroneous propagation. |
| GO:0034198 cellular response to amino acid starvation | IMP PMID:25329545 p58IPK is an inhibitor of the eIF2Ξ± kinase GCN2 and its loca... | UNDECIDED | Summary: The experimental annotation requires full-text adjudication. Reason: The cached original publication is abstract-only. Its emphasis on a different stress response or transcriptional output is insufficient to establish that the annotated assay was absent. The previous confident removal is withdrawn pending recovery of the full text and verification of the specific annotated process. |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000117 | ACCEPT | Summary: PERK is a primary responder to ER stress, and this broader response term remains valid alongside more specific UPR annotations. Reason: The general ER-stress response term is still accurate for EIF2AK3. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:19061639 Role of SERCA1 truncated isoform in the proapoptotic calcium... | ACCEPT | Summary: PERK is a primary responder to ER stress, and this broader response term remains valid alongside more specific UPR annotations. Reason: The general ER-stress response term is still accurate for EIF2AK3. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0036491 regulation of translation initiation in response to endoplasmic reticulum stress | ISS GO_REF:0000024 | ACCEPT | Summary: This is an appropriate ER-stress-specific refinement of PERK's translation attenuation role. Reason: The term matches the best-supported context for EIF2AK3 action on translation initiation. Supporting Evidence: PMID:9930704 ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:10026192 Characterization of a mutant pancreatic eIF-2alpha kinase, P... | ACCEPT | Summary: This branch-specific process term captures core PERK biology in the unfolded protein response. Reason: PERK is the named sensor kinase for this UPR branch. Supporting Evidence: PMID:25925385 interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2Ξ± in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. file:human/EIF2AK3/EIF2AK3-deep-research-falcon.md A canonical pathway is ER stress, PERK activation, eIF2alpha(Ser51) phosphorylation, reduced global translation plus preferential ATF4 translation, adaptive gene expression, and CHOP induction if prolonged. |
| GO:0036499 PERK-mediated unfolded protein response | TAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: This branch-specific process term captures core PERK biology in the unfolded protein response. Reason: PERK is the named sensor kinase for this UPR branch. Supporting Evidence: PMID:25925385 interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2Ξ± in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:25925385 Crystal structures reveal transient PERK luminal domain tetr... | ACCEPT | Summary: This branch-specific process term captures core PERK biology in the unfolded protein response. Reason: PERK is the named sensor kinase for this UPR branch. Supporting Evidence: PMID:25925385 interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2Ξ± in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:31023583 ER and Nutrient Stress Promote Assembly of Respiratory Chain... | ACCEPT | Summary: This branch-specific process term captures core PERK biology in the unfolded protein response. Reason: PERK is the named sensor kinase for this UPR branch. Supporting Evidence: PMID:25925385 interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2Ξ± in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. |
| GO:0036499 PERK-mediated unfolded protein response | IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo... | ACCEPT | Summary: This branch-specific process term captures core PERK biology in the unfolded protein response. Reason: PERK is the named sensor kinase for this UPR branch. Supporting Evidence: PMID:25925385 interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2Ξ± in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation. |
| GO:0042149 cellular response to glucose starvation | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | KEEP AS NON CORE | Summary: Glucose starvation can engage PERK signaling in tumor or metabolic stress settings, but this is contextual rather than the core role of EIF2AK3. Reason: Retain as specialized stress-context biology. Supporting Evidence: PMID:22915762 Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic switch and is a potential target for antiangiogenic cancer therapy. |
| GO:0045943 positive regulation of transcription by RNA polymerase I | IMP PMID:22915762 The unfolded protein response induces the angiogenic switch ... | UNDECIDED | Summary: The experimental annotation requires full-text adjudication. Reason: The cached original publication is abstract-only. Its emphasis on a different stress response or transcriptional output is insufficient to establish that the annotated assay was absent. The previous confident removal is withdrawn pending recovery of the full text and verification of the specific annotated process. |
| GO:0045947 negative regulation of translational initiation | TAS PMID:19816510 Essential role of the unfolded protein response regulator GR... | MODIFY | Summary: PERK negatively regulates translational initiation specifically under stress, so the stress-specific child term is preferable. Reason: Use the more precise stress-contextualized process term. Proposed replacements: negative regulation of translational initiation in response to stress |
| GO:0048009 insulin-like growth factor receptor signaling pathway | ISS GO_REF:0000024 | UNDECIDED | Summary: The transferred process requires donor-specific evidence review. Reason: The earlier rationale rejected this annotation because it was peripheral to canonical ER-stress sensing or because direct support was not identified. Neither argument establishes a false transfer. The underlying ortholog or rule evidence must be recovered to distinguish a supported contextual role from an erroneous propagation. |
| GO:0070417 cellular response to cold | IMP PMID:25329545 p58IPK is an inhibitor of the eIF2Ξ± kinase GCN2 and its loca... | KEEP AS NON CORE | Summary: PERK contributes to the response to hypothermic culture stress. Reason: PMID:25329545 reports overlapping PERK and GCN2 functions and compensatory expression in hypothermic protein-production conditions. This is a supported contextual response; its peripheral nature is not an over-annotation. Supporting Evidence: PMID:25329545 PERK and GCN2 have overlapping functions since knockdown of one of these at the mRNA level is compensated for by the cell by up-regulating levels of the other. |
| GO:1900182 positive regulation of protein localization to nucleus | ISS GO_REF:0000024 | UNDECIDED | Summary: The transferred process requires donor-specific evidence review. Reason: The earlier rationale rejected this annotation because it was peripheral to canonical ER-stress sensing or because direct support was not identified. Neither argument establishes a false transfer. The underlying ortholog or rule evidence must be recovered to distinguish a supported contextual role from an erroneous propagation. |
| GO:1902235 regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IMP PMID:23000344 Ursolic acid induces ER stress response to activate ASK1-JNK... | KEEP AS NON CORE | Summary: PERK can promote ER-stress-induced apoptosis under unresolved stress, but this is a downstream contextual outcome rather than a core homeostatic function. Reason: Retain as non-core chronic-stress biology. Supporting Evidence: PMID:23000344 Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and caspase-3 activation in T24 cells. |
| GO:1990737 response to manganese-induced endoplasmic reticulum stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: A manganese-specific ER-stress response term is too context-specific to retain as a stable reviewed annotation for EIF2AK3. Reason: Prefer broader and better-supported ER-stress process terms. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | UNDECIDED | Summary: The nuclear IBA remains unresolved after focused research and direct review of HPA evidence. Reason: The ancestral assertion at PTN000113601 includes PERK, and soluble eIF2alpha-kinase paralogs provide nuclear evidence. PERK has an established ER-membrane topology, but primary ER localization does not establish exclusive residence. The OpenScientist report identifies HPA nucleoplasm staining; direct inspection confirms CAB009204 signal in A-431 and U2OS, with standard Approved ICC rather than enhanced genetic/tagging validation. Antibody specificity and the molecular form producing the signal remain unresolved. The report incorrectly treats GO:0005634 as nucleoplasm-only: nuclear envelope GO:0005635 is part_of nucleus. A verified nuclear-envelope pool would therefore support the broader nucleus term, although ER continuity alone does not prove such a pool. Retain UNDECIDED rather than treating absent direct GO annotations or membrane topology as evidence of phylogenetic loss. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000113601 Β· PTN000113601 UNRESOLVED PTN000113601 is the genuine family-level nucleus IBD. PERK-specific HPA nucleoplasm signal is supportive but lacks enhanced specificity validation; topology constrains soluble full-length localization but does not exclude a nuclear-envelope pool. No target-specific localization loss has been established. Supporting Evidence: file:human/EIF2AK3/EIF2AK3-hypotheses/function-hypothesis-go-0005634/openscientist.md The one quasi-experimental nuclear signal for PERK itself is **Human Protein Atlas** immunofluorescence |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PERK occupies the cytoplasmic endoplasmic-reticulum membrane. Reason: Cytoplasm includes the ER, and PERK has a cytoplasmic kinase domain. The broad cellular-component annotation is compatible with its more specific ER-membrane location and should not be rejected or replaced on the basis of compartment specificity alone. Supporting Evidence: UniProt:Q9NZJ5 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA PMID:9930704 Protein translation and folding are coupled by an endoplasmi... | MODIFY | Summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the generic ER compartment. Reason: Use the more specific cellular component term. Proposed replacements: endoplasmic reticulum membrane |
| GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site | IDA PMID:39116259 PERK-ATAD3A interaction provides a subcellular safe haven fo... | KEEP AS NON CORE | Summary: Stress-induced PERK-ATAD3A recruitment to mitochondria-associated ER contact sites is supported, but it is contextual rather than the constitutive core location of EIF2AK3. Reason: Retain as a specific non-core stress localization. Supporting Evidence: PMID:39116259 PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: PERK occupies the cytoplasmic endoplasmic-reticulum membrane. Reason: Cytoplasm includes the ER, and PERK has a cytoplasmic kinase domain. The broad cellular-component annotation is compatible with its more specific ER-membrane location and should not be rejected or replaced on the basis of compartment specificity alone. Supporting Evidence: UniProt:Q9NZJ5 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | MODIFY | Summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the generic ER compartment. Reason: Use the more specific cellular component term. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IC PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | MODIFY | Summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the generic ER compartment. Reason: Use the more specific cellular component term. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | TAS PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s... | MODIFY | Summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the generic ER compartment. Reason: Use the more specific cellular component term. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:11907036 Dimerization and release of molecular chaperone inhibition f... | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:22934019 The endoplasmic reticulum stress response in aging and age-r... | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381086 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381087 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-381111 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9921802 | ACCEPT | Summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct core cellular component. Reason: This is the best-supported core localization for EIF2AK3. Supporting Evidence: PMID:9930704 Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9700131 | REMOVE | Summary: This Reactome-based cytosol placement reflects an EIF2AK3-ALK fusion context rather than wild-type PERK localization. Reason: Do not transfer fusion-protein context to the native gene product. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Generic membrane can be refined to endoplasmic reticulum membrane for PERK. Reason: Use the specific established membrane location. Proposed replacements: endoplasmic reticulum membrane |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear cytoplasm is compatible with the ER localization of PERK. Reason: A perinuclear distribution of ER-resident PERK is compatible with its established topology; the general cellular geography is not contradicted by the ER-membrane annotation. Retain this ortholog transfer as a contextual localization. This is retained as an ortholog-derived localization, not a direct target perinuclear imaging claim; the UniProt excerpt supports only the compatible ER context. Supporting Evidence: UniProt:Q9NZJ5 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:1903894 regulation of IRE1-mediated unfolded protein response | IMP PMID:30118681 Coordination between Two Branches of the Unfolded Protein Re... | NEW | Summary: PERK modulates the IRE1 arm of the unfolded protein response through RPAP2-mediated attenuation, supporting a contextual cross-talk annotation that should remain non-core. Reason: This is literature-supported PN context, but it is secondary to the core PERK ISR/translation attenuation role. Supporting Evidence: PMID:30118681 Here, we report that PERK governs IRE1's attenuation through a phosphatase known as RPAP2 (RNA polymerase II-associated protein 2). |
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