EIF2AK3

Existing Annotations Review

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.
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 eIF2α 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 eIF2α kinases PKR (dsRNA-dependent protein kinase/eIF2α kinase 2) and PERK and hence prevent or delay eIF2α 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-eIF2α-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	REMOVE	Summary: PERK is a serine-directed eIF2alpha kinase, not a bona fide protein tyrosine kinase; Tyr619 literature concerns regulation of PERK rather than tyrosine kinase activity toward substrates. Reason: This term misstates the catalytic specificity of EIF2AK3.
GO:0004713 protein tyrosine kinase activity	IEA GO_REF:0000116	REMOVE	Summary: PERK is a serine-directed eIF2alpha kinase, not a bona fide protein tyrosine kinase; Tyr619 literature concerns regulation of PERK rather than tyrosine kinase activity toward substrates. Reason: This term misstates the catalytic specificity of EIF2AK3.
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...	MARK AS OVER ANNOTATED	Summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative to retain as a meaningful reviewed function. Reason: Prefer specific interaction or process terms over broad binding placeholders.
GO:0005515 protein binding	IPI PMID:25393282 TBL2 is a novel PERK-binding protein that modulates stress-s...	MARK AS OVER ANNOTATED	Summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative to retain as a meaningful reviewed function. Reason: Prefer specific interaction or process terms over broad binding placeholders.
GO:0005515 protein binding	IPI PMID:26268696 TMEM33: a new stress-inducible endoplasmic reticulum transme...	MARK AS OVER ANNOTATED	Summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative to retain as a meaningful reviewed function. Reason: Prefer specific interaction or process terms over broad binding placeholders.
GO:0005515 protein binding	IPI PMID:27238082 Compounds Triggering ER Stress Exert Anti-Melanoma Effects a...	MARK AS OVER ANNOTATED	Summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative to retain as a meaningful reviewed function. Reason: Prefer specific interaction or process terms over broad binding placeholders.
GO:0005524 ATP binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: ATP binding is expected for a kinase but adds little biological information beyond the catalytic kinase annotations retained here. Reason: This term is technically true but uninformative for core curation.
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	MARK AS OVER ANNOTATED	Summary: Chaperone interactions may occur, but the IEA-only Hsp90 binding annotation is not needed as a stable reviewed function for PERK. Reason: IEA-only annotation with insufficient experimental support for retention as a reviewed annotation.
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	MODIFY	Summary: PERK regulates translational initiation specifically in the context of ER stress, so the ER-stress-specific child term is a better fit. Reason: Refine the broad translation-initiation regulation term to the stress-contextualized version. Proposed replacements: regulation of translation initiation in response to endoplasmic reticulum stress
GO:0006983 ER overload response	IDA PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ...	REMOVE	Summary: Evidence supports ER stress and unfolded protein response signaling, not the distinct NF-kappaB-linked ER overload response term. Reason: This term overstates a different ER stress program than the one best supported for PERK.
GO:0006983 ER overload response	IDA PMID:11907036 Dimerization and release of molecular chaperone inhibition f...	REMOVE	Summary: Evidence supports ER stress and unfolded protein response signaling, not the distinct NF-kappaB-linked ER overload response term. Reason: This term overstates a different ER stress program than the one best supported for PERK.
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	MODIFY	Summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather than broad negative regulation of translation. Reason: Refine to the stress-contextual process term. Proposed replacements: negative regulation of translation in response to stress
GO:0017148 negative regulation of translation	IEA GO_REF:0000117	MODIFY	Summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather than broad negative regulation of translation. Reason: Refine to the stress-contextual process term. Proposed replacements: negative regulation of translation in response to stress
GO:0017148 negative regulation of translation	TAS PMID:12086964 Loss of kinase activity in a patient with Wolcott-Rallison s...	MODIFY	Summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather than broad negative regulation of translation. Reason: Refine to the stress-contextual process term. Proposed replacements: negative regulation of translation in response to stress
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	REMOVE	Summary: A direct conserved role for human EIF2AK3 in negative regulation of myelination is not sufficiently established relative to its well-supported ER-stress/ISR function. Reason: Current support is too weak and indirect for retention.
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	REMOVE	Summary: EIF2AK3 contributes to the integrated stress response broadly, but amino acid starvation is primarily sensed by GCN2 rather than PERK. Reason: This term mis-centers PERK outside its best-supported stress input.
GO:0034198 cellular response to amino acid starvation	IMP PMID:25329545 p58IPK is an inhibitor of the eIF2α kinase GCN2 and its loca...	REMOVE	Summary: PMID:25329545 studies cold-shock/hypothermic stress and explicitly identifies GCN2, not PERK, as the kinase activated by that condition, so this amino-acid-starvation annotation appears to be a curation error. Reason: REMOVE is appropriate because the cited experiment does not test amino acid starvation and does not support EIF2AK3 as the primary sensor for that 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 eIF2α 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	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 eIF2α 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 eIF2α 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 eIF2α 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 eIF2α 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 ...	REMOVE	Summary: This term is not a good fit for PERK biology; downstream transcriptional outputs are mediated through stress transcription factors and not RNA polymerase I regulation. Reason: The annotation is functionally mismatched and overly indirect.
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	REMOVE	Summary: Evidence for a direct conserved role of EIF2AK3 in insulin-like growth factor receptor signaling is weak relative to its established ER-stress and ISR function. Reason: Current support does not justify retaining this as a reviewed annotation.
GO:0070417 cellular response to cold	IMP PMID:25329545 p58IPK is an inhibitor of the eIF2α kinase GCN2 and its loca...	MARK AS OVER ANNOTATED	Summary: Cold-shock phenotypes do not justify treating PERK as a canonical cellular cold-response gene. Reason: This context is peripheral to the best-supported conserved role of EIF2AK3.
GO:1900182 positive regulation of protein localization to nucleus	ISS GO_REF:0000024	REMOVE	Summary: Nuclear relocalization effects are secondary downstream outcomes and do not support a direct core annotation to this broad transport term. Reason: This is too indirect for retention as a reviewed EIF2AK3 process annotation.
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	REMOVE	Summary: PERK signals to nuclear transcription programs but is not itself an active nuclear protein. Reason: The core location of EIF2AK3 is ER membrane, not nucleus.
GO:0005737 cytoplasm	IBA GO_REF:0000033	MODIFY	Summary: PERK has a cytosolic kinase domain, but the gene product is an ER transmembrane protein, so ER membrane is the better location term. Reason: Refine broad cytoplasmic placement to the correct membrane location. Proposed replacements: 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	MODIFY	Summary: PERK has a cytosolic kinase domain, but the gene product is an ER transmembrane protein, so ER membrane is the better location term. Reason: Refine broad cytoplasmic placement to the correct membrane location. Proposed replacements: 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	MARK AS OVER ANNOTATED	Summary: Perinuclear cytoplasm is too imprecise compared with the established ER membrane localization of PERK. Reason: The more specific ER membrane location should be preferred.
GO:0140467 integrated stress response signaling	IDA PMID:9930704 Protein translation and folding are coupled by an endoplasmi...	NEW	Summary: PERK is a central ISR sensor kinase because ER stress activates PERK to phosphorylate EIF2S1/eIF2alpha, attenuating translation and initiating integrated stress response signaling. Reason: This PN-aligned process is strongly supported in the PERK literature and is not well represented by the existing GOA block. 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: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).

📄 View Raw YAML

id: Q9NZJ5
gene_symbol: EIF2AK3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EIF2AK3 encodes PERK, an endoplasmic-reticulum-resident type I transmembrane stress-sensor
  kinase. Its luminal domain recognizes misfolded proteins and ER stress causes PERK activation, leading
  to phosphorylation of EIF2S1/eIF2alpha, attenuation of translation initiation, and engagement of the
  PERK arm of the unfolded protein response and integrated stress response. Developmental, apoptotic,
  tumor, and ER-mitochondria contact-site phenotypes are retained here only as contextual outputs where
  they are literature-supported, not as core functions.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: PMID:10026192
  title: Characterization of a mutant pancreatic eIF-2alpha kinase, PEK, and co-localization with somatostatin
    in islet delta cells.
  findings: []
- id: PMID:9819435
  title: Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit
    kinase, PEK, involved in translational control.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:10677345
  title: 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.
  findings: []
- id: PMID:11907036
  title: Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic
    initiation factor-2 kinase in response to endoplasmic reticulum stress.
  findings: []
- id: PMID:12086964
  title: Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation
    in the EIF2AK3 gene.
  findings: []
- id: PMID:25329545
  title: p58IPK is an inhibitor of the eIF2α kinase GCN2 and its localization and expression underpin
    protein synthesis and ER processing capacity.
  findings: []
- id: PMID:25925385
  title: Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum
    stress signaling.
  findings:
  - statement: Transient tetramerization of the PERK luminal domain promotes PERK and eIF2alpha phosphorylation
      during UPR activation.
    supporting_text: Additionally, PERK mutants reduce tetramer formation in vitro and reduce PERK and
      eIf2a phosphorylation in cells.
    reference_section_type: ABSTRACT
- id: PMID:31023583
  title: ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α
    Axis.
  findings: []
- id: PMID:39116259
  title: PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress.
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: PMID:25393282
  title: TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during
    endoplasmic reticulum stress.
  findings: []
- id: PMID:26268696
  title: 'TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of
    the unfolded protein response signaling.'
  findings: []
- id: PMID:27238082
  title: Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.
  findings: []
- id: PMID:23103912
  title: PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated
    unfolded protein response.
  findings: []
- id: PMID:22169477
  title: H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum
    stress response.
  findings: []
- id: PMID:27917829
  title: The ER stress sensor PERK luminal domain functions as a molecular chaperone to interact with
    misfolded proteins.
  findings:
  - statement: The PERK luminal domain directly recognizes misfolded proteins.
    supporting_text: the PERK luminal domain can recognize and selectively interact with misfolded proteins
      but not native proteins.
    reference_section_type: ABSTRACT
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: PMID:22915762
  title: The unfolded protein response induces the angiogenic switch in human tumor cells through the
    PERK/ATF4 pathway.
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:19816510
  title: Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal
    apoptosis.
  findings: []
- id: PMID:19061639
  title: Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria
    during ER stress.
  findings: []
- id: PMID:22934019
  title: The endoplasmic reticulum stress response in aging and age-related diseases.
  findings: []
- id: PMID:23000344
  title: Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in
    human bladder cancer T24 cells.
  findings: []
- id: PMID:9930704
  title: Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.
  findings:
  - statement: PERK is an ER-resident eIF2alpha kinase activated by ER stress to attenuate translation.
    supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
      on serine residue 51, inhibiting translation of messenger RNA into protein.
    reference_section_type: ABSTRACT
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:22013210
  title: 'The unfolded protein response: integrating stress signals through the stress sensor IRE1α.'
  findings: []
- id: Reactome:R-HSA-381086
  title: Dissociation of PERK:BiP Heterodimer
  findings: []
- id: Reactome:R-HSA-381087
  title: Dimerization of PERK
  findings: []
- id: Reactome:R-HSA-381111
  title: EIF2AK3 (PERK) phosphorylates EIF2S1 (eIF2-alpha)Phosphorylation of eIF2-alpha by PERK
  findings: []
- id: Reactome:R-HSA-9921802
  title: IFI6 binds HSPA5
  findings: []
- id: Reactome:R-HSA-9700131
  title: ALK mutants bind type I TKIs
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:30118681
  title: Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell
    Fate.
  findings:
  - statement: PERK attenuates the IRE1 branch of the UPR through RPAP2-dependent regulation.
    supporting_text: Here, we report that PERK governs IRE1's attenuation through a phosphatase known
      as RPAP2 (RNA polymerase II-associated protein 2).
    reference_section_type: ABSTRACT
- id: file:human/EIF2AK3/EIF2AK3-notes.md
  title: Curator notes for EIF2AK3 literature and PN review
  findings: []
existing_annotations:
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase
      term rather than a generic kinase annotation.
    action: MODIFY
    reason: Use the child term that captures PERK's established substrate specificity.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: TAS
  original_reference_id: PMID:10026192
  review:
    summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase
      term rather than a generic kinase annotation.
    action: MODIFY
    reason: Use the child term that captures PERK's established substrate specificity.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:9819435
  review:
    summary: PERK is a protein kinase, but the curated core activity is the more specific eIF2alpha kinase
      term rather than a generic kinase annotation.
    action: MODIFY
    reason: Use the child term that captures PERK's established substrate specificity.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: PERK is a serine/threonine kinase, but the more specific eIF2alpha kinase term is the best
      curated representation of its catalytic activity.
    action: MODIFY
    reason: GO:0004694 captures the specific kinase activity directly tied to PERK biology.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: PERK is a serine/threonine kinase, but the more specific eIF2alpha kinase term is the best
      curated representation of its catalytic activity.
    action: MODIFY
    reason: GO:0004694 captures the specific kinase activity directly tied to PERK biology.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:10026192
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:10026192
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:10677345
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:10677345
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:11907036
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:11907036
      supporting_text: 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).
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IMP
  original_reference_id: PMID:12086964
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: The mutated kinase, although it partly retains the ability of autophosphorylation,
        is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha).
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IMP
  original_reference_id: PMID:25329545
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:25329545
      supporting_text: p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily
        C, member 3]} is known to inhibit the eIF2α kinases PKR (dsRNA-dependent protein kinase/eIF2α
        kinase 2) and PERK and hence prevent or delay eIF2α phosphorylation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:25925385
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: Additionally, PERK mutants reduce tetramer formation in vitro and reduce PERK and
        eIf2a phosphorylation in cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:31023583
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:31023583
      supporting_text: The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L),
        promoting SCs and enhanced mitochondrial respiration.
      reference_section_type: ABSTRACT
- term:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  evidence_type: IDA
  original_reference_id: PMID:39116259
  review:
    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.
    action: ACCEPT
    reason: EIF2AK3/PERK is the canonical ER-stress-responsive eIF2alpha kinase.
    supported_by:
    - reference_id: PMID:39116259
      supporting_text: 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).
      reference_section_type: ABSTRACT
- term:
    id: GO:0004713
    label: protein tyrosine kinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: PERK is a serine-directed eIF2alpha kinase, not a bona fide protein tyrosine kinase; Tyr619
      literature concerns regulation of PERK rather than tyrosine kinase activity toward substrates.
    action: REMOVE
    reason: This term misstates the catalytic specificity of EIF2AK3.
- term:
    id: GO:0004713
    label: protein tyrosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: PERK is a serine-directed eIF2alpha kinase, not a bona fide protein tyrosine kinase; Tyr619
      literature concerns regulation of PERK rather than tyrosine kinase activity toward substrates.
    action: REMOVE
    reason: This term misstates the catalytic specificity of EIF2AK3.
- term:
    id: GO:0004715
    label: non-membrane spanning protein tyrosine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: Wild-type PERK is a single-pass ER transmembrane kinase, so non-membrane-spanning protein
      tyrosine kinase activity is incorrect.
    action: REMOVE
    reason: This term conflicts with the architecture and known activity of EIF2AK3.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11907036
  review:
    summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative
      to retain as a meaningful reviewed function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific interaction or process terms over broad binding placeholders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25393282
  review:
    summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative
      to retain as a meaningful reviewed function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific interaction or process terms over broad binding placeholders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26268696
  review:
    summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative
      to retain as a meaningful reviewed function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific interaction or process terms over broad binding placeholders.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27238082
  review:
    summary: Multiple specific PERK interactions are documented, but generic protein binding is too uninformative
      to retain as a meaningful reviewed function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer specific interaction or process terms over broad binding placeholders.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: ATP binding is expected for a kinase but adds little biological information beyond the catalytic
      kinase annotations retained here.
    action: MARK_AS_OVER_ANNOTATED
    reason: This term is technically true but uninformative for core curation.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:23103912
  review:
    summary: Partner-specific regulatory enzyme interactions exist, but the broad enzyme binding term
      is not the best way to capture PERK biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: Specific process or partner-focused annotations are more informative than generic enzyme binding.
- term:
    id: GO:0019903
    label: protein phosphatase binding
  evidence_type: IPI
  original_reference_id: PMID:22169477
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Retain as specific non-core regulatory context.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:11907036
  review:
    summary: PERK oligomerization is mechanistically real, but identical protein binding is an enabling
      context rather than a standalone core function.
    action: KEEP_AS_NON_CORE
    reason: Homomerization supports activation without defining PERK's main molecular output.
- term:
    id: GO:0045182
    label: translation regulator activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: PERK does regulate translation, but the best molecular function curation is its specific
      eIF2alpha kinase activity rather than a generic translation regulator term.
    action: MODIFY
    reason: Replace the broad activity term with the specific catalytic activity.
    proposed_replacement_terms:
    - id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:27917829
  review:
    summary: Direct misfolded-protein recognition by the luminal domain is supported experimentally and
      fits PERK's role as an ER stress sensor.
    action: ACCEPT
    reason: This term captures an experimentally supported sensing mechanism upstream of PERK activation.
    supported_by:
    - reference_id: PMID:27917829
      supporting_text: the PERK luminal domain can recognize and selectively interact with misfolded proteins
        but not native proteins.
      reference_section_type: ABSTRACT
- term:
    id: GO:0051879
    label: Hsp90 protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Chaperone interactions may occur, but the IEA-only Hsp90 binding annotation is not needed
      as a stable reviewed function for PERK.
    action: MARK_AS_OVER_ANNOTATED
    reason: IEA-only annotation with insufficient experimental support for retention as a reviewed annotation.
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific
      eIF2alpha kinase annotation.
    action: ACCEPT
    reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:10026192
  review:
    summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific
      eIF2alpha kinase annotation.
    action: ACCEPT
    reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:10677345
  review:
    summary: PERK is a serine kinase, so this broader catalytic term is valid alongside the more specific
      eIF2alpha kinase annotation.
    action: ACCEPT
    reason: The enzyme phosphorylates eIF2alpha on Ser51 during ER stress.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0001501
    label: skeletal system development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Retain as downstream organismal phenotype context, not core function.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet
        function and bone development in humans
      reference_section_type: ABSTRACT
- term:
    id: GO:0001503
    label: ossification
  evidence_type: IMP
  original_reference_id: PMID:12086964
  review:
    summary: Ossification defects are part of the Wolcott-Rallison phenotype and reflect tissue dependence
      on PERK signaling rather than PERK's core molecular job.
    action: KEEP_AS_NON_CORE
    reason: Keep as a non-core physiological consequence.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet
        function and bone development in humans
      reference_section_type: ABSTRACT
- term:
    id: GO:0001525
    label: angiogenesis
  evidence_type: IMP
  original_reference_id: PMID:22915762
  review:
    summary: Tumor angiogenesis downstream of PERK-ATF4 signaling is supported in specialized stress contexts
      but is not a constitutive core role of EIF2AK3.
    action: KEEP_AS_NON_CORE
    reason: Retain as contextual stress-pathway output.
    supported_by:
    - reference_id: PMID:22915762
      supporting_text: Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic
        switch and is a potential target for antiangiogenic cancer therapy.
      reference_section_type: ABSTRACT
- term:
    id: GO:0002063
    label: chondrocyte development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Chondrocyte developmental phenotypes fit the broader Wolcott-Rallison developmental syndrome,
      but they are not the core evolved molecular role of PERK.
    action: KEEP_AS_NON_CORE
    reason: Keep developmental consequences separate from core ISR/UPR biology.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet
        function and bone development in humans
      reference_section_type: ABSTRACT
- term:
    id: GO:0006446
    label: regulation of translational initiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PERK regulates translational initiation specifically in the context of ER stress, so the
      ER-stress-specific child term is a better fit.
    action: MODIFY
    reason: Refine the broad translation-initiation regulation term to the stress-contextualized version.
    proposed_replacement_terms:
    - id: GO:0036491
      label: regulation of translation initiation in response to endoplasmic reticulum stress
- term:
    id: GO:0006983
    label: ER overload response
  evidence_type: IDA
  original_reference_id: PMID:10677345
  review:
    summary: Evidence supports ER stress and unfolded protein response signaling, not the distinct NF-kappaB-linked
      ER overload response term.
    action: REMOVE
    reason: This term overstates a different ER stress program than the one best supported for PERK.
- term:
    id: GO:0006983
    label: ER overload response
  evidence_type: IDA
  original_reference_id: PMID:11907036
  review:
    summary: Evidence supports ER stress and unfolded protein response signaling, not the distinct NF-kappaB-linked
      ER overload response term.
    action: REMOVE
    reason: This term overstates a different ER stress program than the one best supported for PERK.
- term:
    id: GO:0007029
    label: endoplasmic reticulum organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: UNDECIDED
    reason: More direct evidence would be needed to retain or remove confidently.
- term:
    id: GO:0010575
    label: positive regulation of vascular endothelial growth factor production
  evidence_type: IMP
  original_reference_id: PMID:22915762
  review:
    summary: PERK can promote VEGF production in tumor stress settings, but that is a contextual downstream
      output rather than a core homeostatic role.
    action: KEEP_AS_NON_CORE
    reason: Retain as stress-contextual non-core biology.
    supported_by:
    - reference_id: PMID:22915762
      supporting_text: Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic
        switch and is a potential target for antiangiogenic cancer therapy.
      reference_section_type: ABSTRACT
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:22915762
  review:
    summary: PERK signaling influences transcriptional programs via ATF4, NRF2, and CHOP, but this broad
      term obscures the specific stress pathways involved.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer pathway-specific process terms over a generic gene-expression label.
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather
      than broad negative regulation of translation.
    action: MODIFY
    reason: Refine to the stress-contextual process term.
    proposed_replacement_terms:
    - id: GO:0032055
      label: negative regulation of translation in response to stress
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather
      than broad negative regulation of translation.
    action: MODIFY
    reason: Refine to the stress-contextual process term.
    proposed_replacement_terms:
    - id: GO:0032055
      label: negative regulation of translation in response to stress
- term:
    id: GO:0017148
    label: negative regulation of translation
  evidence_type: TAS
  original_reference_id: PMID:12086964
  review:
    summary: PERK-dependent translation attenuation is best captured in a stress-specific term rather
      than broad negative regulation of translation.
    action: MODIFY
    reason: Refine to the stress-contextual process term.
    proposed_replacement_terms:
    - id: GO:0032055
      label: negative regulation of translation in response to stress
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Calcium perturbation can trigger PERK, but EIF2AK3 is not best captured as a general calcium-mediated
      signaling gene.
    action: MARK_AS_OVER_ANNOTATED
    reason: This is too broad relative to the direct ER-stress sensing role.
- term:
    id: GO:0030282
    label: bone mineralization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core developmental phenotype context.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet
        function and bone development in humans
      reference_section_type: ABSTRACT
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:10677345
  review:
    summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response
      is well supported.
    action: ACCEPT
    reason: This process term accurately captures a central branch of EIF2AK3 biology.
    supported_by:
    - reference_id: PMID:10677345
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:11907036
  review:
    summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response
      is well supported.
    action: ACCEPT
    reason: This process term accurately captures a central branch of EIF2AK3 biology.
    supported_by:
    - reference_id: PMID:11907036
      supporting_text: In the absence of stress, PEK associates with ER chaperones GRP78 (BiP) and GRP94,
        and this binding is released in response to ER stress.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: TAS
  original_reference_id: PMID:19816510
  review:
    summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response
      is well supported.
    action: ACCEPT
    reason: This process term accurately captures a central branch of EIF2AK3 biology.
    supported_by:
    - reference_id: PMID:19816510
      supporting_text: GRP78-depleted PCs activate UPR including the induction of GRP94, PDI, CHOP and
        GADD34, feedback suppression of eIF2alpha phosphorylation and apoptotic cell death.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:22169477
  review:
    summary: PERK is one of the core ER stress sensors, so involvement in the unfolded protein response
      is well supported.
    action: ACCEPT
    reason: This process term accurately captures a central branch of EIF2AK3 biology.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031018
    label: endocrine pancreas development
  evidence_type: IMP
  original_reference_id: PMID:12086964
  review:
    summary: Pancreatic developmental and islet phenotypes in Wolcott-Rallison syndrome are real, but
      they are downstream tissue consequences rather than core PERK molecular function.
    action: KEEP_AS_NON_CORE
    reason: Keep tissue-development outcomes separate from core ISR/UPR roles.
    supported_by:
    - reference_id: PMID:12086964
      supporting_text: Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet
        function and bone development in humans
      reference_section_type: ABSTRACT
- term:
    id: GO:0031642
    label: negative regulation of myelination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: A direct conserved role for human EIF2AK3 in negative regulation of myelination is not sufficiently
      established relative to its well-supported ER-stress/ISR function.
    action: REMOVE
    reason: Current support is too weak and indirect for retention.
- term:
    id: GO:0032055
    label: negative regulation of translation in response to stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: PERK-dependent eIF2alpha phosphorylation directly attenuates translation under stress; this
      matches the central ISR and proteostasis role of EIF2AK3.
    action: ACCEPT
    reason: This is a core PN-aligned process for PERK.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0032057
    label: negative regulation of translational initiation in response to stress
  evidence_type: TAS
  original_reference_id: PMID:10677345
  review:
    summary: PERK directly suppresses translation initiation during stress through eIF2alpha phosphorylation.
    action: ACCEPT
    reason: This is the mechanistically precise form of PERK-mediated translation attenuation.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0032057
    label: negative regulation of translational initiation in response to stress
  evidence_type: TAS
  original_reference_id: PMID:12086964
  review:
    summary: PERK directly suppresses translation initiation during stress through eIF2alpha phosphorylation.
    action: ACCEPT
    reason: This is the mechanistically precise form of PERK-mediated translation attenuation.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: EIF2AK3 contributes to the integrated stress response broadly, but amino acid starvation
      is primarily sensed by GCN2 rather than PERK.
    action: REMOVE
    reason: This term mis-centers PERK outside its best-supported stress input.
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: IMP
  original_reference_id: PMID:25329545
  review:
    summary: PMID:25329545 studies cold-shock/hypothermic stress and explicitly identifies GCN2, not PERK,
      as the kinase activated by that condition, so this amino-acid-starvation annotation appears to be
      a curation error.
    action: REMOVE
    reason: REMOVE is appropriate because the cited experiment does not test amino acid starvation and
      does not support EIF2AK3 as the primary sensor for that process.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: PERK is a primary responder to ER stress, and this broader response term remains valid alongside
      more specific UPR annotations.
    action: ACCEPT
    reason: The general ER-stress response term is still accurate for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:19061639
  review:
    summary: PERK is a primary responder to ER stress, and this broader response term remains valid alongside
      more specific UPR annotations.
    action: ACCEPT
    reason: The general ER-stress response term is still accurate for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036491
    label: regulation of translation initiation in response to endoplasmic reticulum stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This is an appropriate ER-stress-specific refinement of PERK's translation attenuation role.
    action: ACCEPT
    reason: The term matches the best-supported context for EIF2AK3 action on translation initiation.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:10026192
  review:
    summary: This branch-specific process term captures core PERK biology in the unfolded protein response.
    action: ACCEPT
    reason: PERK is the named sensor kinase for this UPR branch.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
        of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
        to tetrameric state may be a key regulatory step in UPR activation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: TAS
  original_reference_id: PMID:22934019
  review:
    summary: This branch-specific process term captures core PERK biology in the unfolded protein response.
    action: ACCEPT
    reason: PERK is the named sensor kinase for this UPR branch.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
        of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
        to tetrameric state may be a key regulatory step in UPR activation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:25925385
  review:
    summary: This branch-specific process term captures core PERK biology in the unfolded protein response.
    action: ACCEPT
    reason: PERK is the named sensor kinase for this UPR branch.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
        of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
        to tetrameric state may be a key regulatory step in UPR activation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:31023583
  review:
    summary: This branch-specific process term captures core PERK biology in the unfolded protein response.
    action: ACCEPT
    reason: PERK is the named sensor kinase for this UPR branch.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
        of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
        to tetrameric state may be a key regulatory step in UPR activation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036499
    label: PERK-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:39116259
  review:
    summary: This branch-specific process term captures core PERK biology in the unfolded protein response.
    action: ACCEPT
    reason: PERK is the named sensor kinase for this UPR branch.
    supported_by:
    - reference_id: PMID:25925385
      supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
        of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
        to tetrameric state may be a key regulatory step in UPR activation.
      reference_section_type: ABSTRACT
- term:
    id: GO:0042149
    label: cellular response to glucose starvation
  evidence_type: IMP
  original_reference_id: PMID:22915762
  review:
    summary: Glucose starvation can engage PERK signaling in tumor or metabolic stress settings, but this
      is contextual rather than the core role of EIF2AK3.
    action: KEEP_AS_NON_CORE
    reason: Retain as specialized stress-context biology.
    supported_by:
    - reference_id: PMID:22915762
      supporting_text: Collectively, these results show that the PERK/ATF4 arm of UPR mediates the angiogenic
        switch and is a potential target for antiangiogenic cancer therapy.
      reference_section_type: ABSTRACT
- term:
    id: GO:0045943
    label: positive regulation of transcription by RNA polymerase I
  evidence_type: IMP
  original_reference_id: PMID:22915762
  review:
    summary: This term is not a good fit for PERK biology; downstream transcriptional outputs are mediated
      through stress transcription factors and not RNA polymerase I regulation.
    action: REMOVE
    reason: The annotation is functionally mismatched and overly indirect.
- term:
    id: GO:0045947
    label: negative regulation of translational initiation
  evidence_type: TAS
  original_reference_id: PMID:19816510
  review:
    summary: PERK negatively regulates translational initiation specifically under stress, so the stress-specific
      child term is preferable.
    action: MODIFY
    reason: Use the more precise stress-contextualized process term.
    proposed_replacement_terms:
    - id: GO:0032057
      label: negative regulation of translational initiation in response to stress
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Evidence for a direct conserved role of EIF2AK3 in insulin-like growth factor receptor signaling
      is weak relative to its established ER-stress and ISR function.
    action: REMOVE
    reason: Current support does not justify retaining this as a reviewed annotation.
- term:
    id: GO:0070417
    label: cellular response to cold
  evidence_type: IMP
  original_reference_id: PMID:25329545
  review:
    summary: Cold-shock phenotypes do not justify treating PERK as a canonical cellular cold-response
      gene.
    action: MARK_AS_OVER_ANNOTATED
    reason: This context is peripheral to the best-supported conserved role of EIF2AK3.
- term:
    id: GO:1900182
    label: positive regulation of protein localization to nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Nuclear relocalization effects are secondary downstream outcomes and do not support a direct
      core annotation to this broad transport term.
    action: REMOVE
    reason: This is too indirect for retention as a reviewed EIF2AK3 process annotation.
- term:
    id: GO:1902235
    label: regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23000344
  review:
    summary: PERK can promote ER-stress-induced apoptosis under unresolved stress, but this is a downstream
      contextual outcome rather than a core homeostatic function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core chronic-stress biology.
    supported_by:
    - reference_id: PMID:23000344
      supporting_text: Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and
        caspase-3 activation in T24 cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:1990737
    label: response to manganese-induced endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: A manganese-specific ER-stress response term is too context-specific to retain as a stable
      reviewed annotation for EIF2AK3.
    action: MARK_AS_OVER_ANNOTATED
    reason: Prefer broader and better-supported ER-stress process terms.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PERK signals to nuclear transcription programs but is not itself an active nuclear protein.
    action: REMOVE
    reason: The core location of EIF2AK3 is ER membrane, not nucleus.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: PERK has a cytosolic kinase domain, but the gene product is an ER transmembrane protein,
      so ER membrane is the better location term.
    action: MODIFY
    reason: Refine broad cytoplasmic placement to the correct membrane location.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:9930704
  review:
    summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the
      generic ER compartment.
    action: MODIFY
    reason: Use the more specific cellular component term.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0044233
    label: mitochondria-associated endoplasmic reticulum membrane contact site
  evidence_type: IDA
  original_reference_id: PMID:39116259
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Retain as a specific non-core stress localization.
    supported_by:
    - reference_id: PMID:39116259
      supporting_text: PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact
        sites.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: PERK has a cytosolic kinase domain, but the gene product is an ER transmembrane protein,
      so ER membrane is the better location term.
    action: MODIFY
    reason: Refine broad cytoplasmic placement to the correct membrane location.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the
      generic ER compartment.
    action: MODIFY
    reason: Use the more specific cellular component term.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IC
  original_reference_id: PMID:11907036
  review:
    summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the
      generic ER compartment.
    action: MODIFY
    reason: Use the more specific cellular component term.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:12086964
  review:
    summary: The protein is more precisely localized to the endoplasmic reticulum membrane than to the
      generic ER compartment.
    action: MODIFY
    reason: Use the more specific cellular component term.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:11907036
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:22013210
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:22934019
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381086
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381087
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-381111
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9921802
  review:
    summary: PERK is an ER-resident transmembrane protein; endoplasmic reticulum membrane is the correct
      core cellular component.
    action: ACCEPT
    reason: This is the best-supported core localization for EIF2AK3.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident
        protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700131
  review:
    summary: This Reactome-based cytosol placement reflects an EIF2AK3-ALK fusion context rather than
      wild-type PERK localization.
    action: REMOVE
    reason: Do not transfer fusion-protein context to the native gene product.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: Generic membrane can be refined to endoplasmic reticulum membrane for PERK.
    action: MODIFY
    reason: Use the specific established membrane location.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Perinuclear cytoplasm is too imprecise compared with the established ER membrane localization
      of PERK.
    action: MARK_AS_OVER_ANNOTATED
    reason: The more specific ER membrane location should be preferred.
- term:
    id: GO:0140467
    label: integrated stress response signaling
  evidence_type: IDA
  original_reference_id: PMID:9930704
  review:
    action: NEW
    summary: PERK is a central ISR sensor kinase because ER stress activates PERK to phosphorylate EIF2S1/eIF2alpha,
      attenuating translation and initiating integrated stress response signaling.
    reason: This PN-aligned process is strongly supported in the PERK literature and is not well represented
      by the existing GOA block.
    supported_by:
    - reference_id: PMID:9930704
      supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
        on serine residue 51, inhibiting translation of messenger RNA into protein.
      reference_section_type: ABSTRACT
- term:
    id: GO:1903894
    label: regulation of IRE1-mediated unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:30118681
  review:
    action: 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.
    supported_by:
    - reference_id: PMID:30118681
      supporting_text: Here, we report that PERK governs IRE1's attenuation through a phosphatase known
        as RPAP2 (RNA polymerase II-associated protein 2).
      reference_section_type: ABSTRACT
core_functions:
- description: ER-membrane PERK phosphorylates EIF2S1/eIF2alpha to attenuate translation initiation during
    ER stress and drive the PERK arm of the integrated stress response.
  molecular_function:
    id: GO:0004694
    label: eukaryotic translation initiation factor 2alpha kinase activity
  directly_involved_in:
  - id: GO:0140467
    label: integrated stress response signaling
  - id: GO:0036491
    label: regulation of translation initiation in response to endoplasmic reticulum stress
  - id: GO:0036499
    label: PERK-mediated unfolded protein response
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:9930704
    supporting_text: ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha
      on serine residue 51, inhibiting translation of messenger RNA into protein.
    reference_section_type: ABSTRACT
  - reference_id: PMID:25925385
    supporting_text: interface mutations that disrupt tetramer formation in vitro reduce phosphorylation
      of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric
      to tetrameric state may be a key regulatory step in UPR activation.
    reference_section_type: ABSTRACT
- description: The PERK luminal domain directly recognizes misfolded proteins, coupling ER protein-folding
    stress to activation of PERK-mediated UPR signaling.
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  directly_involved_in:
  - id: GO:0036499
    label: PERK-mediated unfolded protein response
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:27917829
    supporting_text: the PERK luminal domain can recognize and selectively interact with misfolded proteins
      but not native proteins.
    reference_section_type: ABSTRACT

Gene Description

Existing Annotations Review

Core Functions

ER-membrane PERK phosphorylates EIF2S1/eIF2alpha to attenuate translation initiation during ER stress and drive the PERK arm of the integrated stress response.

The PERK luminal domain directly recognizes misfolded proteins, coupling ER protein-folding stress to activation of PERK-mediated UPR signaling.

References

📚 Additional Documentation

Notes

EIF2AK3 notes

Core literature picture

PN framing used here

Contextual roles retained as non-core

Cautionary removals

📄 View Raw YAML