Mapk3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: nucleus is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0035556 intracellular signal transduction	IBA GO_REF:0000033	MODIFY	Summary: intracellular signal transduction is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000622075 SUPPORTS TRANSFER A deep kinase node, not an ERK-specific one: the local PAINT cache lists PTN000622075 in the files of four families - PTHR24055 (PANTHER name "MITOGEN-ACTIVATED PROTEIN KINASE", the family UniProt assigns to the target), PTHR24056 ("CELL DIVISION PROTEIN KINASE"), PTHR24057 ("GLYCOGEN SYNTHASE KINASE-3 ALPHA") and PTHR44167. THIS row's IBD seeds span fungal, slime-mould, worm, fly and vertebrate kinases of those groups; the node's plant seeds (AGI_LocusCode) sit in its GO:0004674, GO:0005634 and GO:0005737 rows, not in the GO:0035556 one under review, whose WITH/FROM carries no AGI or TAIR entry. Across a clade that broad the generic parent is the only biological-process term that holds for every member, so the node placement is sound and only the term is uninformative for mouse Mapk3. MGI:MGI:1346859 · mouse Mapk3 (the review target itself) SUPPORTS TRANSFER The target's own MGI record is among the IBD seeds, the expected marker that experimental grounding exists on the target itself: Mapk3 carries an IGI at GO:0070371 ERK1 and ERK2 cascade (PMID:19047410) and an IGI at GO:0000165 MAPK cascade (PMID:21220101), both descendants of this term, which are among the descendant evidences behind the IBD. MGI:MGI:1346858 · mouse Mapk1 (ERK2, the target's closest paralog) SUPPORTS TRANSFER ERK1/ERK2 are functionally interchangeable in the cascade; the transfer between them is not at issue. FB:FBgn0003256 · Drosophila rolled (rl, the fly ERK) SUPPORTS TRANSFER The single fly ERK ortholog, one of the seeds that anchors the cascade role deep in the metazoan tree. UniProtKB:P27361 · human MAPK3 (ERK1) SUPPORTS TRANSFER The 1:1 human ortholog seed. Its presence, with the fly and mouse ERK seeds, is why the informative claim available here is the ERK1/2 cascade: GO:0070371 is a genuine descendant of GO:0035556 (via GO:0000165 MAPK cascade), so the MODIFY is a parent-to-child narrowing rather than a change of claim. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: protein serine/threonine kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0007166 cell surface receptor signaling pathway	IBA GO_REF:0000033	MODIFY	Summary: cell surface receptor signaling pathway is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN008603019 SUPPORTS TRANSFER A different, much shallower node than the one behind the GO:0035556 row: PTN008603019 appears only in the PTHR24055 PAINT file (PANTHER family name "MITOGEN-ACTIVATED PROTEIN KINASE", the target's own family) and its IBD seeds are exactly the ERK orthologs - fly rolled, mouse Mapk1 and Mapk3, human MAPK1 and MAPK3. The clade is the right one; what is wrong is that GO:0007166 names the upstream receptor pathway that recruits ERK rather than ERK's own step in it. MGI:MGI:1346859 · mouse Mapk3 (the review target itself) SUPPORTS TRANSFER The target's own MGI record is among the IBD seeds, the expected marker that experimental grounding exists on the target itself: Mapk3 carries an IGI at GO:0070371 ERK1 and ERK2 cascade (PMID:19047410) and an IGI at GO:0000165 MAPK cascade (PMID:21220101), which are among the descendant evidences behind the IBD. MGI:MGI:1346858 · mouse Mapk1 (ERK2, the target's closest paralog) SUPPORTS TRANSFER Second mouse ERK seed; ERK1 and ERK2 act in the same cascade downstream of the same receptor classes. FB:FBgn0003256 · Drosophila rolled (rl, the fly ERK) SUPPORTS TRANSFER The fly ERK ortholog seed; like the vertebrate seeds it acts downstream of RTK input rather than at the receptor itself. UniProtKB:P27361 · human MAPK3 (ERK1) SUPPORTS TRANSFER The 1:1 human ortholog seed. Note that GO:0070371 is not a descendant of GO:0007166 - its is_a/part_of ancestors run through GO:0000165 and GO:0035556 - so unlike the GO:0035556 row this MODIFY is a lateral re-scope from the receptor pathway onto the effector cascade the seeds actually share, not a narrowing, which is why no granularity failure mode is asserted. UniProtKB:P28482 · human MAPK1 (ERK2) SUPPORTS TRANSFER The human paralog seed, counterpart of the mouse Mapk1 record above. With it this block enumerates all six WITH/FROM sources; the same lateral re-scope applies to it, since it too acts downstream of receptor input rather than at the receptor itself. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0001784 phosphotyrosine residue binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: phosphotyrosine residue binding matches the experimentally supported paxillin-pTyr association of ERK1, but is not the core kinase function. Reason: This ARBA prediction mirrors the IMP evidence from PMID:14636584 that inactive ERK associates with tyrosine-phosphorylated paxillin; retained as non-core to stay consistent with that experimental row. Supporting Evidence: PMID:14636584 this is mediated by the tyrosine phosphorylation-dependent association of inactive ERK and the focal adhesion complex protein paxillin
GO:0004672 protein kinase activity	IEA GO_REF:0000002	MODIFY	Summary: protein kinase activity is less specific than ERK MAP kinase activity. Reason: MAPK1/MAPK3 are ERK-family MAP kinases with proline-directed serine/threonine protein kinase activity. Proposed replacements: MAP kinase activity Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0004707 MAP kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP binding is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: nucleus is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005739 mitochondrion	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: mitochondrion is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005769 early endosome	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: early endosome is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005770 late endosome	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: late endosome is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005794 Golgi apparatus	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Golgi apparatus is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005856 cytoskeleton	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cytoskeleton is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005901 caveola	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: caveola is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005925 focal adhesion	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: focal adhesion is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0031143 pseudopodium	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: pseudopodium is a documented site of beta-arrestin-scaffolded ERK1/2 during chemotaxis, not a primary compartment. Reason: PMID:12821670 shows a PAR-2/beta-arrestin/ERK1/2 complex enriched in pseudopodia of migrating cells, so this electronically predicted localization has direct experimental backing; kept non-core because it is a transient, stimulus-dependent pool. Supporting Evidence: PMID:12821670 PAR-2/beta-arrestin/ERK1/2 scaffolding complex is enriched in the pseudopodia
GO:0032872 regulation of stress-activated MAPK cascade	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: regulation of stress-activated MAPK cascade attributes cross-cascade regulatory activity to ERK1 on machine-learning evidence only. Reason: ERK1 belongs to the classical mitogen-responsive cascade; crosstalk toward the JNK/p38 stress cascades is context-dependent and no direct mouse evidence for ERK1 regulating a stress-activated cascade is available locally, so this ARBA prediction over-reaches.
GO:0042473 outer ear morphogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: outer ear morphogenesis reflects the ERK1/2 requirement in neural crest development, a pleiotropic developmental output. Reason: Concordant with the IGI evidence from PMID:18952847 in which ERK-cascade disruption perturbs craniofacial neural crest derivatives including the outer ear; a developmental phenotype rather than a core kinase function. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0043330 response to exogenous dsRNA	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: response to exogenous dsRNA is corroborated by mouse TLR3/Trif pathway experiments in which ERK participates. Reason: The matching IDA row from PMID:12872135 (Trif/Lps2 mutant macrophage responses to dsRNA) gives this electronically predicted response term experimental grounding in mouse innate immunity, though it is a context-specific signaling output.
GO:0051493 regulation of cytoskeleton organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: regulation of cytoskeleton organization by ERK1/2 is documented through paxillin and actin-remodeling substrates. Reason: ERK1/2 phosphorylate cytoskeletal regulators and drive actin reorganization during chemotaxis, as in the pseudopodial ERK pool of PMID:12821670, so the prediction is biologically sound though it is a downstream regulatory output rather than the core activity. Supporting Evidence: PMID:12821670 PAR-2 activation promotes ERK1/2- and beta-arrestin-dependent reorganization of the actin cytoskeleton
GO:0060020 Bergmann glial cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Bergmann glial cell differentiation depends on FGF/ERK signaling, matching mouse genetic evidence. Reason: Consistent with the IGI row from PMID:24431450 showing Shp2-dependent ERK activation is required for Bergmann glia specification in the mouse cerebellum; a lineage-specific developmental output of the cascade.
GO:0061308 cardiac neural crest cell development involved in heart development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cardiac neural crest development involvement echoes the mouse ERK1/2 neural crest requirement. Reason: The IGI evidence from PMID:18952847 links ERK-cascade disruption to conotruncal cardiac outflow tract defects of neural crest origin, so this electronic prediction is grounded, though it is a pleiotropic developmental phenotype.
GO:0071356 cellular response to tumor necrosis factor	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: cellular response to tumor necrosis factor is supported by mouse myotube experiments showing TNF-modulated ERK1/2 phosphorylation. Reason: Aligned with the IGI row from PMID:24349514 in which TNF-alpha treatment of C2C12 myotubes alters phospho-ERK1/2 levels; a stimulus-response context rather than the defining function.
GO:0072584 caveolin-mediated endocytosis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: caveolin-mediated endocytosis links to the caveolar ERK pool described in compartmentalized ERK signaling. Reason: ERK1/2 localize to caveolae and modulate caveolar trafficking, matching the caveola compartment rows retained in this review per PMID:19565474; the process term is kept as non-core regulatory context because ERK participates via localized signaling rather than as endocytic machinery.
GO:0090170 regulation of Golgi inheritance	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: regulation of Golgi inheritance reflects Golgi-localized ERK function during mitotic Golgi fragmentation. Reason: Golgi-resident ERK signaling regulating Golgi fragmentation before mitosis is established ERK1/2 biology summarized in PMID:19565474; a compartment-specific regulatory role, not the core kinase function.
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	MODIFY	Summary: protein serine kinase activity is less specific than ERK MAP kinase activity. Reason: MAPK1/MAPK3 are ERK-family MAP kinases with proline-directed serine/threonine protein kinase activity. Proposed replacements: MAP kinase activity Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:2000641 regulation of early endosome to late endosome transport	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: regulation of early-to-late endosome transport corresponds to the endosomal ERK1/2 signaling pool. Reason: Endosome-localized ERK signaling influencing endosomal maturation is part of the compartmentalized ERK biology already retained for the endosome localization rows; a non-core trafficking-regulation output.
GO:0005515 protein binding	IPI PMID:22307056 ERK1 and ERK2 regulate embryonic stem cell self-renewal thro...	MARK AS OVER ANNOTATED	Summary: protein binding records a physical association but is too generic to describe the gene product function. Reason: The evidence supports regulated signaling-complex assembly, not a meaningful standalone protein binding function; more informative molecular and pathway terms capture the biology. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0000165 MAPK cascade	IEA GO_REF:0000107	MODIFY	Summary: MAPK cascade is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0002841 negative regulation of T cell mediated immune response to tumor cell	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of T cell mediated immune response to tumor cell is a hyper-specific tumor-immunology claim carried only by orthology pipelines. Reason: This composite term derives from a single-context study propagated by Ensembl Compara; attributing a standing tumor-immunosuppression function to ERK1, whose T cell roles are broadly activation-promoting, over-interprets the transfer.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000107	ACCEPT	Summary: protein serine/threonine kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005635 nuclear envelope	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: nuclear envelope localization reflects transient passage of ERK1 through nuclear pores rather than residency. Reason: ERK1/2 contact nucleoporins only while shuttling between cytoplasm and nucleoplasm; annotating the nuclear envelope as a compartment of ERK1 converts a transit interaction into a standing localization.
GO:0005654 nucleoplasm	IEA GO_REF:0000120	ACCEPT	Summary: nucleoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0007173 epidermal growth factor receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: EGF receptor signaling is the paradigmatic upstream activator of the ERK1/2 cascade. Reason: ERK1 is the terminal kinase of RAS-RAF-MEK signaling downstream of EGFR; the pathway-membership term is biologically solid but names only one of many receptor inputs, so it is non-core relative to the ERK1 and ERK2 cascade itself.
GO:0019902 phosphatase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: phosphatase binding captures the well-characterized docking of DUSP/MKP phosphatases on ERK1. Reason: Inactivation of ERK1/2 through docking-based interactions with dual-specificity phosphatases is central, direct ERK biology, but it describes a regulatory interaction rather than the catalytic function, so it stays non-core.
GO:0030509 BMP signaling pathway	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: BMP signaling pathway membership for ERK1 rests on crosstalk, not pathway componency. Reason: ERK1/2 phosphorylate SMAD linker regions to modulate BMP outputs, but that is crosstalk from the RTK-ERK axis; calling ERK1 a BMP pathway component via Compara propagation inflates the relationship.
GO:0034198 cellular response to amino acid starvation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to amino acid starvation is a niche stress context propagated without mouse support. Reason: ERK activation state shifts under many stresses; elevating one starvation paradigm from an ortholog study into a standing ERK1 annotation exaggerates its place in the functional profile of this gene.
GO:0042770 signal transduction in response to DNA damage	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: signal transduction in response to DNA damage is anchored by the ERK1/2-dependent SGK1 induction after DNA damage. Reason: Concordant with the IDA row from PMID:15383658 where DNA damage induces SGK1 through ERK1/2-mediated regulation in the p53-FOXO3a axis; a stress-context signaling role, not the core cascade definition. Supporting Evidence: PMID:15383658 this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation
GO:0042802 identical protein binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: ERK dimerization is directly supported by PMID:26267534, but identical protein binding is a secondary signaling-state property rather than the core ERK1 kinase function. Reason: Retain as supported non-core biology; the core molecular function remains ERK MAP kinase activity and protein phosphorylation. Supporting Evidence: PMID:26267534 Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling
GO:0045944 positive regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: positive regulation of RNA Pol II transcription summarizes the activation of TCF/Elk-1-driven immediate-early genes by ERK1. Reason: Nuclear ERK1/2 phosphorylate Elk-1 and related transcription factors to switch on immediate-early gene transcription (compare Reactome R-MMU-198706 in the reference list); a major downstream output, though indirect relative to the kinase activity.
GO:0051403 stress-activated MAPK cascade	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Stress-activated MAPK cascade denotes the JNK/p38 modules, whereas ERK1 is a terminal kinase of the mitogen-activated ERK1/2 cascade (GO:0070371). Reason: Although some stresses can activate ERK1/2, placing ERK1 inside the stress-activated MAPK cascade conflates it with the JNK/p38 modules; the accepted ERK1 and ERK2 cascade term already captures the correct module, so this electronic row is flagged as over-annotation. Matches the treatment of the identical term on the ERK2 paralog Mapk1, which carries the same IEA and ISO rows.
GO:0061514 interleukin-34-mediated signaling pathway	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IL-34 pathway membership enumerates one of many receptor systems that converge on ERK1/2. Reason: IL-34/CSF1R engagement activates ERK like dozens of other cytokine and growth factor receptors; propagating each such upstream pathway onto ERK1 electronically produces over-annotation without adding functional information.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: positive regulation of ERK1 and ERK2 cascade casts the terminal output kinase as an upstream activator of its own cascade. Reason: ERK1 executes the cascade rather than positively regulating it, and its best-documented feedback phosphorylation of RAF, SOS and MEK is inhibitory; the regulatory term likely stems from indirect readouts and over-annotates.
GO:0070498 interleukin-1-mediated signaling pathway	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IL-1 pathway membership lists a single upstream stimulus among the many that activate ERK1/2. Reason: IL-1 receptor signaling reaches ERK via IRAK/TRAF6/TAK1, but ERK1 participation there is generic downstream kinase engagement; the pathway-specific annotation adds context, not function, and over-annotates by enumeration.
GO:0070849 response to epidermal growth factor	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: response to epidermal growth factor is the founding physiological context of ERK activation. Reason: EGF stimulation of ERK1/2 phosphorylation is the archetypal cascade trigger and amply conserved in mouse; the term describes the stimulus context of the core activity, hence non-core but sound.
GO:0071260 cellular response to mechanical stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: cellular response to mechanical stimulus generalizes a mechanotransduction context onto ERK1. Reason: Mechanical stress activates many kinase pathways including ERK in specific cell types, but the propagated term gives ERK1 a standing mechanoresponse function that neither local evidence nor core ERK biology singles out.
GO:0140297 DNA-binding transcription factor binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: DNA-binding transcription factor binding reflects docking of ERK1 onto substrate transcription factors such as Elk-1. Reason: ERK1/2 engage transcription factor substrates through D-motif and DEF-site docking before phosphorylating them (see Reactome R-MMU-198706 on ELK1 activation); an informative substrate-interaction term kept as non-core.
GO:0150078 positive regulation of neuroinflammatory response	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: positive regulation of neuroinflammatory response echoes direct mouse ICH evidence for the CCR1/TPR1/ERK1/2 axis. Reason: Backed by the IDA row from PMID:31898284 in which ERK1/2 activation downstream of CCR1 promotes neuroinflammation after intracerebral hemorrhage; a pathological signaling context, so non-core.
GO:1904262 negative regulation of TORC1 signaling	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: negative regulation of TORC1 signaling inverts the predominant ERK-mTORC1 relationship. Reason: Canonical ERK1/2 signaling activates mTORC1 by phosphorylating and inhibiting TSC2, directly and via RSK; a propagated negative-regulation claim reflects a specialized context and misleads as a standing ERK1 function.
GO:0032991 protein-containing complex	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: protein-containing complex is a root-level component term conveying no ERK1-specific information. Reason: Like the protein binding rows already marked over-annotated in this review, assigning the generic complex root records only that ERK1 associates with scaffolds and partners; the informative statements are the specific localization and interaction annotations.
GO:0106310 protein serine kinase activity	ISS GO_REF:0000024	MODIFY	Summary: protein serine kinase activity is less specific than ERK MAP kinase activity. Reason: MAPK1/MAPK3 are ERK-family MAP kinases with proline-directed serine/threonine protein kinase activity. Proposed replacements: MAP kinase activity Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0004674 protein serine/threonine kinase activity	TAS Reactome:R-MMU-198706	ACCEPT	Summary: protein serine/threonine kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0006468 protein phosphorylation	ISO GO_REF:0000096	ACCEPT	Summary: protein phosphorylation is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0006468 protein phosphorylation	ISO GO_REF:0000119	ACCEPT	Summary: protein phosphorylation is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0016310 phosphorylation	ISO GO_REF:0000119	MODIFY	Summary: Phosphorylation is too broad for an ERK kinase annotation. Reason: The relevant process is protein phosphorylation catalyzed by ERK MAP kinase activity. Proposed replacements: protein phosphorylation Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0018105 peptidyl-serine phosphorylation	ISO GO_REF:0000096	ACCEPT	Summary: peptidyl-serine phosphorylation is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0031281 positive regulation of cyclase activity	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of cyclase activity is an obscure, single-context ortholog transfer. Reason: Neither local evidence nor canonical ERK1/2 biology establishes cyclase regulation as an ERK1 function; the transferred human observation is too peripheral to keep as a standing annotation.
GO:0038083 peptidyl-tyrosine autophosphorylation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: peptidyl-tyrosine autophosphorylation is not a defensible core ERK annotation. Reason: The Falcon synthesis supports ERK as a proline-directed protein kinase in MAPK signaling; this term is too indirect, too broad, or mechanistically mismatched for the gene product. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0097542 ciliary tip	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: ciliary tip localization stems from human ciliary studies without mouse corroboration. Reason: Reports of ERK at ciliary subdomains come from specialized human cell systems; ciliary residence is not part of established ERK1 cell biology and the transferred subcompartment claim is over-fine.
GO:0000045 autophagosome assembly	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: autophagosome assembly credits ERK1 with a biogenesis role beyond its regulatory input. Reason: ERK signaling modulates autophagy induction, as kept for the xenophagy and positive-regulation rows, but direct involvement in building autophagosomes overstates a kinase acting upstream of the machinery.
GO:0000165 MAPK cascade	ISO GO_REF:0000096	MODIFY	Summary: MAPK cascade is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0000165 MAPK cascade	ISO GO_REF:0000119	MODIFY	Summary: MAPK cascade is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0002841 negative regulation of T cell mediated immune response to tumor cell	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Ortholog transfer of a narrow tumor-directed T cell suppression phenotype to mouse ERK1. Reason: The human-to-mouse transfer inherits one experimental context; ERK1/2 signaling in T cells is predominantly required for activation, so a blanket negative-regulation-of-antitumor-immunity annotation overstates the evidence.
GO:0004674 protein serine/threonine kinase activity	ISO GO_REF:0000119	ACCEPT	Summary: protein serine/threonine kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0004707 MAP kinase activity	ISO GO_REF:0000096	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0004707 MAP kinase activity	ISO GO_REF:0000119	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005524 ATP binding	ISO GO_REF:0000096	ACCEPT	Summary: ATP binding is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005635 nuclear envelope	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-derived nuclear envelope assignment for a kinase that shuttles through, not into, the envelope. Reason: The transferred human annotation likely captures nucleoporin-associated ERK during nucleocytoplasmic shuttling; the accepted nucleus, nucleoplasm, and cytoplasm rows already describe the steady-state distribution.
GO:0005654 nucleoplasm	ISO GO_REF:0000096	ACCEPT	Summary: nucleoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005654 nucleoplasm	ISO GO_REF:0000119	ACCEPT	Summary: nucleoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005737 cytoplasm	ISO GO_REF:0000096	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005886 plasma membrane	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: plasma membrane matches the membrane-associated ERK1/2 pool at receptors and scaffolds. Reason: A fraction of ERK1/2 is recruited to plasma membrane receptor complexes and caveolae during activation, as reflected in the retained caveola rows and the deep-research synthesis; kept as a non-core, activation-linked localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005901 caveola	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: caveola localization from rat orthology matches the retained caveolar ERK rows. Reason: This transfer duplicates the caveola annotations already kept as non-core in this review (the IEA and TAS rows citing compartmentalized ERK signaling); handled identically for consistency. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005929 cilium	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: cilium localization is an ortholog-propagated assignment outside the canonical ERK compartments. Reason: Steady-state ERK1 distribution is cytoplasmic and nuclear with organelle-associated pools; a general ciliary localization for mouse ERK1 lacks supporting evidence here and likely traces to a limited human dataset.
GO:0007173 epidermal growth factor receptor signaling pathway	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-derived EGFR pathway membership for ERK1, the canonical downstream kinase. Reason: The ortholog transfer restates textbook biology in which EGF-bound receptor signaling culminates in ERK1/2 activation; kept as a non-core receptor-context annotation alongside the response-to-EGF rows.
GO:0009636 response to toxic substance	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: response to toxic substance parallels mouse studies of ERK activation by oxidative toxicity. Reason: ERK1/2 activation under oxidative or toxic insult is documented in the mouse ischemia and neuronal toxicity papers already in this reference list (PMID:12223545, PMID:11726647); a stress-response context, hence non-core.
GO:0010507 negative regulation of autophagy	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of autophagy is one side of a context-dependent ERK effect, transferred without mouse support. Reason: ERK signaling can restrain autophagy through mTORC1 activation in some settings, yet the local mouse evidence in PMID:22033934 shows ERK promoting autophagy; keeping the opposite-sign electronic row as a standing function over-annotates the negative arm.
GO:0010508 positive regulation of autophagy	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: positive regulation of autophagy agrees with the mouse xenophagy genetics for ERK. Reason: Matches the IGI evidence from PMID:22033934 where autophagy of L. monocytogenes depends selectively on the ERK pathway in macrophages; a supported context-specific regulatory output. Supporting Evidence: PMID:22033934 autophagy against L. monocytogenes was dependent selectively on the ERK pathway
GO:0010759 positive regulation of macrophage chemotaxis	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of macrophage chemotaxis is a cell-type-specific output transferred from one human context. Reason: ERK contributes to chemotactic signaling in many motile cells; singling out macrophage chemotaxis as a standing mouse ERK1 function from an ortholog transfer over-specifies the biology.
GO:0015630 microtubule cytoskeleton	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: microtubule cytoskeleton association recalls the original identification of ERK1 as a microtubule-associated protein 2 kinase. Reason: A substantial ERK1/2 fraction is microtubule-associated, in line with the retained cytoskeleton rows and the MAP2 kinase synonym recorded for this protein in UniProt; a non-core localization pool.
GO:0019902 phosphatase binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Ortholog-transferred phosphatase interaction consistent with conserved DUSP docking on ERK1/2. Reason: Human ERK1 binds MKP/DUSP-family phosphatases through the common docking domain and the relevant residues are conserved in mouse; a genuine interaction annotation that is secondary to the kinase activity itself.
GO:0030509 BMP signaling pathway	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-derived BMP pathway assignment that conflates SMAD-linker crosstalk with core pathway membership. Reason: The transferred context reflects ERK-mediated modulation of BMP/SMAD signaling in particular cell systems; ERK1 is not part of the BMP receptor-SMAD transduction chain, so the annotation over-extends.
GO:0031669 cellular response to nutrient levels	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: cellular response to nutrient levels is a diffuse metabolic-context transfer. Reason: ERK activity responds to countless extracellular cues; a generic nutrient-response annotation from human orthology neither pinpoints a mechanism nor reflects characterized mouse ERK1 biology.
GO:0032206 positive regulation of telomere maintenance	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of telomere maintenance is a specialized human-derived claim not established for mouse ERK1. Reason: Reports of ERK phosphorylating telomeric factors such as TRF2 in human cells remain a narrow context; the transferred term promotes this to a standing function without corroboration.
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of proteasomal degradation generalizes substrate-level stabilization events. Reason: ERK phosphorylation can shield individual substrates from ubiquitin-dependent turnover, but a gene-level annotation that ERK1 negatively regulates proteasomal catabolism inflates those substrate-specific effects.
GO:0034198 cellular response to amino acid starvation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Ortholog transfer of an amino acid starvation response observed in one human experimental system. Reason: No local evidence ties mouse ERK1 to starvation signaling, and the phenomenon is a generic stress modulation of the cascade rather than a distinctive ERK1 function.
GO:0035556 intracellular signal transduction	ISO GO_REF:0000096	MODIFY	Summary: intracellular signal transduction is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0036064 ciliary basal body	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: ciliary basal body assignment shares the weakness of the other transferred ciliary rows. Reason: As with the cilium and ciliary tip transfers, basal body residence of ERK1 is not corroborated by mouse data or by the compartmentalized ERK literature used elsewhere in this review.
GO:0038202 TORC1 signaling	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: TORC1 signaling membership for a kinase that only crosstalks with mTORC1. Reason: ERK1 modulates mTORC1 through TSC2/RSK crosstalk but is not a component of TORC1 signal transduction; the transferred pathway-membership term over-assigns.
GO:0042770 signal transduction in response to DNA damage	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-transferred DNA damage signaling role matching the direct mouse-relevant SGK1 evidence. Reason: The transfer parallels the experimentally supported DNA damage response row from PMID:15383658, where ERK1/2 relay p53-dependent signals to SGK1/FOXO3a; retained as non-core stress signaling.
GO:0042802 identical protein binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: ERK dimerization is directly supported by PMID:26267534, but identical protein binding is a secondary signaling-state property rather than the core ERK1 kinase function. Reason: Retain as supported non-core biology; the core molecular function remains ERK MAP kinase activity and protein phosphorylation. Supporting Evidence: PMID:26267534 Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling
GO:0045727 positive regulation of translation	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: positive regulation of translation aligns with MAPK-driven protein synthesis in mouse myelination. Reason: ERK signaling boosts translation via MNK/eIF4E and downstream effectors, and sustained MAPK activation massively up-regulates protein production in mouse Schwann cells (PMID:24493648); a downstream output, kept non-core. Supporting Evidence: PMID:24493648 MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production
GO:0045944 positive regulation of transcription by RNA polymerase II	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Ortholog-transferred transcriptional activation output of nuclear ERK1. Reason: Matches the conserved role of activated ERK entering the nucleus to phosphorylate Pol II-associated transcription factors; kept as a non-core downstream output executed through substrate phosphorylation.
GO:0046697 decidualization	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: decidualization is a rat-derived reproductive-physiology output of ERK signaling. Reason: The mouse-rat transfer reflects experimentally observed ERK involvement in uterine decidualization; as with other tissue-level developmental outputs in this review, it is retained but marked non-core.
GO:0050821 protein stabilization	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: protein stabilization is too vague to stand as an ERK1 function. Reason: Phosphorylation by ERK alters the stability of particular substrates in particular directions; the undirected protein stabilization term communicates no mechanism and is better covered by the kinase and substrate annotations.
GO:0050868 negative regulation of T cell activation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: negative regulation of T cell activation runs against the established requirement for ERK in TCR signaling. Reason: ERK1/2 activity downstream of the TCR promotes T cell activation and thymocyte selection; the transferred negative-regulation claim must derive from a specialized human context and is misleading as a general mouse ERK1 annotation.
GO:0051403 stress-activated MAPK cascade	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Ortholog transfer placing ERK1 inside the stress-activated (SAPK) cascade, which denotes the JNK/p38 modules rather than the ERK1/2 cascade. Reason: The SAPK cascade term is defined by JNK/p38 module membership, and mouse ERK1 is a terminal kinase of the ERK1 and ERK2 cascade (GO:0070371), which is already accepted here. Some stresses do activate ERK1/2, so rather than calling the transfer flatly wrong this is flagged as over-annotation - the same treatment given to the identical term on the ERK2 paralog Mapk1, and to the paired IEA row on this gene.
GO:0061514 interleukin-34-mediated signaling pathway	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-derived IL-34 signaling assignment reflecting generic downstream ERK activation. Reason: The transferred annotation records that ERK is phosphorylated downstream of IL-34-bound CSF1R in a human system; this is generic cascade engagement, not a distinctive mouse ERK1 function.
GO:0065003 protein-containing complex assembly	ISO GO_REF:0000096	MARK AS OVER ANNOTATED	Summary: protein-containing complex assembly is a generic process transfer with no ERK1-specific content. Reason: That ERK1 enters scaffolded signaling complexes is captured by the interaction rows; annotating the gene to complex assembly as a process treats a byproduct of signaling as a function and over-annotates.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Ortholog-transferred claim that ERK1 positively regulates its own cascade. Reason: Known ERK1/2 feedback onto upstream cascade components is predominantly negative; a positive-regulation annotation on the terminal kinase of the cascade most likely reflects an indirect experimental readout in the human source.
GO:0070498 interleukin-1-mediated signaling pathway	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Human-derived IL-1 signaling assignment for ERK1 as a generic downstream kinase. Reason: The transfer captures ERK phosphorylation after IL-1 stimulation in a human context; IL-1 outputs run chiefly through NF-kB and the stress MAPKs, with ERK engagement being ancillary, so the annotation overstates the role of ERK1.
GO:0070849 response to epidermal growth factor	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Ortholog-transferred EGF responsiveness of ERK1. Reason: The human evidence transferring here reflects the canonical EGF-to-ERK axis on which the cascade was defined; retained as a supported stimulus-response annotation secondary to the kinase function.
GO:0097110 scaffold protein binding	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: scaffold protein binding describes ERK1 engagement with KSR- and beta-arrestin-type scaffolds. Reason: Scaffold binding governs where and how long ERK1/2 signal, exemplified locally by the beta-arrestin-scaffolded pseudopodial ERK pool of PMID:12821670; an informative regulatory interaction, non-core to the catalytic function. Supporting Evidence: PMID:12821670 PAR-2/beta-arrestin/ERK1/2 scaffolding complex is enriched in the pseudopodia
GO:0097237 cellular response to toxic substance	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: cellular response to toxic substance mirrors the broader toxic-response row and mouse oxidative-stress data. Reason: Same rationale as the response to toxic substance transfer, with cellular-level ERK activation by oxidative toxicants shown in the neuronal systems cited here (PMID:11726647); kept as non-core stress context.
GO:0120041 positive regulation of macrophage proliferation	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: positive regulation of macrophage proliferation reflects generic mitogenic ERK signaling in one lineage. Reason: Proliferative signaling is the textbook ERK cascade output in essentially every mitogen-responsive cell; a macrophage-specific proliferation term transferred from human adds enumeration, not information.
GO:0140297 DNA-binding transcription factor binding	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Ortholog-transferred transcription factor docking interaction of ERK1. Reason: Conserved docking-groove contacts between ERK1/2 and TCF-family transcription factors underlie immediate-early gene induction; retained as a mechanistically meaningful, non-core interaction annotation.
GO:0150078 positive regulation of neuroinflammatory response	ISO GO_REF:0000119	KEEP AS NON CORE	Summary: Human-transferred neuroinflammatory role congruent with the direct mouse ICH study. Reason: This transfer duplicates biology already shown in mouse by PMID:31898284 (CCR1/TPR1/ERK1/2 after intracerebral hemorrhage); kept as non-core to match the experimental row for the same term.
GO:1904262 negative regulation of TORC1 signaling	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: Ortholog-transferred TORC1-inhibition claim contrary to the usual ERK-TSC2-mTORC1 activation axis. Reason: Whatever human context generated this row, the dominant documented ERK1/2 effect on mTORC1 is stimulatory; transferring the opposite sign onto mouse ERK1 without local support is over-annotation.
GO:0150078 positive regulation of neuroinflammatory response	IDA PMID:31898284 CCR1 Activation Promotes Neuroinflammation Through CCR1/TPR1...	KEEP AS NON CORE	Summary: Direct mouse evidence that ERK1/2 signaling downstream of CCR1/TPR1 promotes neuroinflammation after intracerebral hemorrhage. Reason: The study used an ERK1/2 activator to restore CCR1-driven inflammation blocked by receptor antagonism, placing ERK1/2 causally in the pro-inflammatory pathway; a disease-context output annotation, retained as non-core. Supporting Evidence: PMID:31898284 the mechanism of CCR1/tetratricopeptide repeat 1 (TPR1)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway in CCR1-mediated neuroinflammation
GO:0090370 negative regulation of cholesterol efflux	IMP PMID:20037141 Inhibition of ERK1/2 and activation of liver X receptor syne...	KEEP AS NON CORE	Summary: ERK1/2 activity suppresses macrophage ABCA1 expression and cholesterol efflux. Reason: Direct inhibitor and activator experiments in macrophages show ERK1/2 activation lowers, and inhibition raises, ABCA1-dependent cholesterol efflux; a metabolic regulatory output of the cascade rather than a core function. Supporting Evidence: PMID:20037141 activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression
GO:0050804 modulation of chemical synaptic transmission	IMP PMID:12062026 Knockout of ERK1 MAP kinase enhances synaptic plasticity in ...	KEEP AS NON CORE	Summary: Erk1 knockout mice show enhanced striatal synaptic plasticity, demonstrating synaptic modulation. Reason: Loss of ERK1 facilitates long-term potentiation in the nucleus accumbens and alters striatal plasticity, establishing a genuine but region-specific neuromodulatory role for ERK1; non-core relative to the kinase and cascade functions. Supporting Evidence: PMID:12062026 a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens
GO:0050804 modulation of chemical synaptic transmission	IDA PMID:12062026 Knockout of ERK1 MAP kinase enhances synaptic plasticity in ...	KEEP AS NON CORE	Summary: Direct electrophysiological evidence from the same Erk1 mutant study of altered synaptic transmission. Reason: This IDA row records the direct plasticity measurements in ERK1-deficient striatum from the paper; treated identically to the IMP row for consistency, as a neuronal-context output annotation. Supporting Evidence: PMID:12062026 a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens
GO:0098978 glutamatergic synapse	IMP PMID:12062026 Knockout of ERK1 MAP kinase enhances synaptic plasticity in ...	KEEP AS NON CORE	Summary: glutamatergic synapse reflects ERK1 function at corticostriatal and accumbens synapses. Reason: The plasticity phenotypes of Erk1-null mice localize ERK1 action to glutamatergic synapses of the striatum and nucleus accumbens; a synaptic-context component annotation kept as non-core. Supporting Evidence: PMID:12062026 a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens
GO:0098978 glutamatergic synapse	IDA PMID:12062026 Knockout of ERK1 MAP kinase enhances synaptic plasticity in ...	KEEP AS NON CORE	Summary: Direct-assay counterpart of the glutamatergic synapse annotation from the Erk1 knockout study. Reason: Matches the IMP row from the same paper; the synaptic localization and context of ERK1 during striatal long-term potentiation is well supported but peripheral to the core kinase activity. Supporting Evidence: PMID:12062026 a dramatic enhancement of striatum-dependent long-term memory, which correlates with a facilitation of long-term potentiation in the nucleus accumbens
GO:0005829 cytosol	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	ACCEPT	Summary: cytosol is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0004707 MAP kinase activity	IDA PMID:1717989 Mouse Erk-1 gene product is a serine/threonine protein kinas...	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0048009 insulin-like growth factor receptor signaling pathway	IDA PMID:14997210 Specific roles for the PI3K and the MEK-ERK pathway in IGF-1...	KEEP AS NON CORE	Summary: MEK-ERK signaling mediates specific IGF-1 outputs in the mouse 5T33MM model. Reason: IGF-1 stimulation activated ERK1/2 and MEK-ERK inhibition abolished IGF-1-driven VEGF secretion while reducing proliferation in mouse myeloma cells, placing ERK1 downstream of the IGF-1 receptor; one receptor context among many, hence non-core. Supporting Evidence: PMID:14997210 only the MEK-ERK pathway is involved in IGF-1-stimulated VEGF production
GO:0048009 insulin-like growth factor receptor signaling pathway	ISO PMID:17348861 IGF-I-induced oligodendrocyte progenitor proliferation requi...	KEEP AS NON CORE	Summary: Rat oligodendrocyte progenitor data transferred to mouse for IGF-1 receptor signaling. Reason: In rat oligodendrocyte progenitors IGF-I-driven proliferation requires MEK1/ERK signaling; the ortholog transfer is congruent with the direct mouse IDA row for this pathway term and is kept non-core with it. Supporting Evidence: PMID:17348861 stimulation of oligodendrocyte progenitor proliferation by IGF-I requires Src-like tyrosine kinases as well as the PI3K/Akt and MEK1/ERK signaling pathways
GO:0008286 insulin receptor signaling pathway	IDA PMID:20889126 Insulin signaling to the glomerular podocyte is critical for...	KEEP AS NON CORE	Summary: Insulin signals to podocytes through the MAPK pathway via the insulin receptor. Reason: The podocyte study demonstrates insulin receptor-dependent MAPK-arm signaling important for kidney function, situating ERK1 downstream of the insulin receptor in a defined physiological context; receptor-pathway membership, so non-core. Supporting Evidence: PMID:20889126 insulin signals through the MAPK and PI3K pathways via the insulin receptor
GO:0014044 Schwann cell development	IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ...	KEEP AS NON CORE	Summary: Schwann cell development annotation from the erbB2 conditional mutant study. Reason: The cached abstract covers Neuregulin/ErbB2 control of Schwann cell development without naming ERK1; the full-text basis used by the curator cannot be checked locally, but ERK1/2 are the established effectors of this axis, so the annotation is credible as a non-core developmental role. Supporting Evidence: PMID:24493648 activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination
GO:0042552 myelination	IMP PMID:10704452 A dual role of erbB2 in myelination and in expansion of the ...	KEEP AS NON CORE	Summary: Myelination role inferred from erbB2 mutant neuropathy with ERK as the downstream effector. Reason: erbB2 ablation causes hypomyelination and the annotation reflects ERK1 acting downstream of Neuregulin/ErbB in Schwann cells, a link proven directly by MAPK gain-of-function driving continuous myelin growth in PMID:24493648; a developmental output, non-core. Supporting Evidence: PMID:24493648 sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination
GO:0042552 myelination	IMP PMID:18760695 Neuregulin-1/ErbB signaling serves distinct functions in mye...	KEEP AS NON CORE	Summary: Second myelination row, from the Nrg1/ErbB conditional mutant series. Reason: PMID:18760695 dissects NRG1/ErbB requirements for peripheral versus central myelination; ERK1 is annotated as the downstream kinase of this pathway, consistent with the direct MAPK myelination evidence in PMID:24493648, and is kept as a non-core developmental role. Supporting Evidence: PMID:24493648 sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination
GO:0004674 protein serine/threonine kinase activity	ISO PMID:33331896 Merlin cooperates with neurofibromin and Spred1 to suppress ...	ACCEPT	Summary: protein serine/threonine kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0038133 ERBB2-ERBB3 signaling pathway	IDA PMID:24493648 Activation of MAPK overrides the termination of myelin growt...	KEEP AS NON CORE	Summary: ERK1 acts downstream of ERBB2-ERBB3 in Schwann cell myelination signaling. Reason: The study shows activated MAPK signaling substitutes for ErbB3/Shp2 during Schwann cell development, functionally placing ERK1/2 within the ERBB2-ERBB3 pathway; a receptor-pathway context annotation, non-core. Supporting Evidence: PMID:24493648 activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination
GO:0000165 MAPK cascade	IGI PMID:21220101 Specific functions for ERK/MAPK signaling during PNS develop...	MODIFY	Summary: MAPK cascade is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0005654 nucleoplasm	TAS Reactome:R-MMU-198706	ACCEPT	Summary: nucleoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005515 protein binding	IPI PMID:14636584 Phosphorylation-dependent paxillin-ERK association mediates ...	MARK AS OVER ANNOTATED	Summary: protein binding records a physical association but is too generic to describe the gene product function. Reason: The evidence supports regulated signaling-complex assembly, not a meaningful standalone protein binding function; more informative molecular and pathway terms capture the biology. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0005515 protein binding	IPI PMID:15537391 Vanishin is a novel ubiquitinylated death-effector domain pr...	MARK AS OVER ANNOTATED	Summary: protein binding records a physical association but is too generic to describe the gene product function. Reason: The evidence supports regulated signaling-complex assembly, not a meaningful standalone protein binding function; more informative molecular and pathway terms capture the biology. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0071356 cellular response to tumor necrosis factor	IGI PMID:24349514 MicroRNA-494, upregulated by tumor necrosis factor-α, desens...	KEEP AS NON CORE	Summary: TNF-alpha alters ERK1/2 phosphorylation in mouse C2C12 myotubes. Reason: The full text documents changed p-ERK-1/2 levels upon TNF-alpha incubation during inflammation-induced insulin resistance; a genuine but context-specific cellular response annotation. Supporting Evidence: PMID:24349514 the level of p-ERK-1/2 decreased on incubation with TNF-α at 2 or 20 ng/ml
GO:0004707 MAP kinase activity	IMP PMID:26375174 Regulation of neuronal pH by the metabotropic Zn(2+)-sensing...	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0051453 regulation of intracellular pH	IMP PMID:26375174 Regulation of neuronal pH by the metabotropic Zn(2+)-sensing...	KEEP AS NON CORE	Summary: ERK1/2-dependent up-regulation of NHE activity mediates neuronal pH recovery downstream of mZnR/GPR39. Reason: Zinc-receptor signaling raises Na+/H+ exchanger activity in hippocampal neurons in an ERK1/2-dependent manner, giving a defined physiological pH-regulation output for the kinase; non-core relative to the cascade itself. Supporting Evidence: PMID:26375174 the Na(+)/H(+) exchanger (NHE), is induced by mZnR/GPR39 activation in an extracellular-regulated kinase 1/2-dependent manner in hippocampal neurons
GO:0005886 plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity transfer of plasma membrane association for ERK1. Reason: Consistent with the ISO plasma membrane row and the membrane-associated ERK pool described in the deep research synthesis; a transient signaling localization, so retained as non-core. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005901 caveola	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator similarity-based caveola assignment consistent with the other caveolar rows. Reason: Kept in line with the IEA, ISO and TAS caveola annotations retained as non-core localization context per the compartmentalized ERK literature. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0030278 regulation of ossification	IGI PMID:20053668 Gain-of-function mutation in FGFR3 in mice leads to decrease...	KEEP AS NON CORE	Summary: Elevated Erk1/2 activity downstream of FGFR3 impairs bone matrix mineralization. Reason: In the achondroplasia FGFR3 gain-of-function model, enhanced Erk1/2 activity is causally tied to defective mineralization, supporting a role in ossification regulation; a skeletal-context output of ERK signaling, non-core. Supporting Evidence: PMID:20053668 enhanced Erk1/2 activity is responsible for the impaired bone matrix mineralization
GO:1904417 positive regulation of xenophagy	IGI PMID:22033934 TLR2 and RIP2 pathways mediate autophagy of Listeria monocyt...	KEEP AS NON CORE	Summary: The ERK pathway is selectively required for antibacterial autophagy of Listeria in mouse macrophages. Reason: ERK inhibition or deficiency reduced autophagosome targeting of L. monocytogenes downstream of TLR2/NOD2, giving direct genetic support for a xenophagy-promoting role; an immune-context output rather than core function. Supporting Evidence: PMID:22033934 autophagy against L. monocytogenes was dependent selectively on the ERK pathway
GO:0014032 neural crest cell development	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Neural crest development depends on the RAF/MEK/ERK cascade in mouse. Reason: The genetic series in this paper establishes neural crest development as critically ERK-cascade dependent, with Mapk3 annotated through the combined ERK1/2 analysis; a major but pleiotropic developmental role, hence non-core. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0030878 thyroid gland development	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Thyroid gland defects are among the neural crest derivative phenotypes of ERK pathway disruption. Reason: Thyroid development is one of the pharyngeal, neural crest derived structures perturbed in the ERK cascade mutants of this study; an organ-level developmental consequence, retained as non-core. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0042473 outer ear morphogenesis	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Outer ear defects arise in mice with disrupted ERK1/2 neural crest signaling. Reason: PMID:18952847 reports craniofacial anomalies from RAF/MEK/ERK pathway inactivation in the developing neural crest; this genetic-interaction phenotype is a downstream developmental output of the cascade, so it is kept but not core. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0048538 thymus development	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Thymus development phenotype from the same ERK cascade neural crest series. Reason: Thymic defects in the DiGeorge-spectrum phenocopy of the ERK pathway mutants tie ERK1/2 signaling to pharyngeal organ development; kept as a non-core developmental annotation consistent with its sibling rows. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0060324 face development	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Craniofacial development requires intact ERK cascade signaling in neural crest. Reason: Craniofacial anomalies were replicated across mutants of B-Raf and C-Raf, MEK1/2, ERK2 and SRF in this work, embedding ERK1/2 in facial morphogenesis; a developmental output annotation, non-core. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0061308 cardiac neural crest cell development involved in heart development	IGI PMID:18952847 Mouse and human phenotypes indicate a critical conserved rol...	KEEP AS NON CORE	Summary: Cardiac outflow tract neural crest defects follow ERK cascade inactivation in mice. Reason: The study reports conotruncal anomalies from perturbation of neural crest ERK signaling, replicated across cascade components; retained as a developmental, non-core output of ERK1/2 activity. Supporting Evidence: PMID:18952847 mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway
GO:0060020 Bergmann glial cell differentiation	IGI PMID:24431450 Shp2-dependent ERK signaling is essential for induction of B...	KEEP AS NON CORE	Summary: Genetic evidence that ERK activation downstream of Shp2/FGF drives Bergmann glia specification. Reason: PMID:24431450 shows loss of Shp2 blocks ERK activation in radial glia and prevents Bergmann glia formation, rescued by constitutively active MEK1; a well-supported developmental role executed through the core cascade, hence non-core. Supporting Evidence: PMID:24431450 essential role of Shp2 in BG specification via fibroblast growth factor/extracellular signal-regulated protein kinase signaling
GO:0070371 ERK1 and ERK2 cascade	IGI PMID:19047410 Phosphoinositide 3-kinase-dependent inhibition of dendritic ...	ACCEPT	Summary: ERK1 and ERK2 cascade is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0060425 lung morphogenesis	IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra...	KEEP AS NON CORE	Summary: Lung morphogenesis requires epithelial ERK/MAPK signaling in mouse. Reason: Mutating Erk1 and Erk2 in airway epithelium phenocopies the Mek mutant lung agenesis, demonstrating an ERK1/2 requirement in respiratory development; a pleiotropic organogenesis output, non-core. Supporting Evidence: PMID:25100655 these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium
GO:0060440 trachea formation	IGI PMID:25100655 Crucial requirement of ERK/MAPK signaling in respiratory tra...	KEEP AS NON CORE	Summary: Trachea formation depends on the ERK/MAPK pathway in respiratory progenitors. Reason: The same genetic series shows tracheal progenitor maintenance and differentiation need ERK/MAPK signaling, with Erk1;Erk2 epithelial mutants phenocopying Mek loss; a developmental annotation kept non-core. Supporting Evidence: PMID:25100655 these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium
GO:0005829 cytosol	IDA PMID:22451653 Siglec-15 protein regulates formation of functional osteocla...	ACCEPT	Summary: cytosol is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0070849 response to epidermal growth factor	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator sequence-similarity transfer of EGF responsiveness. Reason: This ISS row repeats the well-founded EGF-responsive behavior of ERK1 orthologs; handled consistently with the other response-to-EGF rows kept as non-core context.
GO:0005634 nucleus	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	ACCEPT	Summary: nucleus is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005739 mitochondrion	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: mitochondrion is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005769 early endosome	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: early endosome is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005770 late endosome	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: late endosome is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005794 Golgi apparatus	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: Golgi apparatus is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005856 cytoskeleton	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: cytoskeleton is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005901 caveola	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: caveola is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0005925 focal adhesion	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: focal adhesion is supported as ERK subcellular localization context but is not a core molecular activity. Reason: PMID:19565474 supports ERK targeting to distinct subcellular compartments; retain this as non-core localization/context rather than the primary kinase function. Supporting Evidence: PMID:19565474 targets at distinct subcellular compartments
GO:0032872 regulation of stress-activated MAPK cascade	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	MARK AS OVER ANNOTATED	Summary: Review-derived claim that compartmentalized ERK signaling regulates stress-activated MAPK cascades. Reason: The cited Yao and Seger review discusses ERK localization broadly; attributing regulation of the JNK/p38 stress cascades to ERK1 itself stretches a general statement about cascade crosstalk beyond what is demonstrated for mouse ERK1.
GO:0051493 regulation of cytoskeleton organization	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: Author statement that cytoskeleton-localized ERK regulates cytoskeletal processes. Reason: The Yao and Seger review describes ERK targeting many compartments whose local substrates in turn regulate diverse cellular processes, including cytoskeletal organization; retained as a supported but non-core regulatory role. Supporting Evidence: PMID:19565474 induce and regulate a large number of cellular processes
GO:0072584 caveolin-mediated endocytosis	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: Author statement connecting caveolar ERK signaling to caveolin-mediated endocytosis. Reason: Follows the same review used for the retained caveola localization rows; the endocytosis process is one of the compartment-linked activities ERK modulates, kept as non-core context. Supporting Evidence: PMID:19565474 induce and regulate a large number of cellular processes
GO:0090170 regulation of Golgi inheritance	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: Author statement on Golgi-localized ERK regulating Golgi partitioning. Reason: The review supporting the retained Golgi apparatus localization row also covers the mitotic Golgi fragmentation role of Golgi-associated ERK; kept as non-core organelle-level regulation. Supporting Evidence: PMID:19565474 induce and regulate a large number of cellular processes
GO:2000641 regulation of early endosome to late endosome transport	TAS PMID:19565474 The ERK signaling cascade--views from different subcellular ...	KEEP AS NON CORE	Summary: Author statement that endosomal ERK modulates endosome maturation and transport. Reason: Same review as the retained early and late endosome compartment rows; the transport-regulation process is the functional counterpart of that localization, kept as non-core. Supporting Evidence: PMID:19565474 induce and regulate a large number of cellular processes
GO:0031143 pseudopodium	IDA PMID:12821670 A beta-arrestin-dependent scaffold is associated with prolon...	KEEP AS NON CORE	Summary: Direct localization of scaffolded ERK1/2 to pseudopodia during PAR-2-induced chemotaxis. Reason: The paper physically isolated pseudopodial proteins and found the beta-arrestin-sequestered ERK1/2 pool enriched at the leading edge; a genuine but context-specific localization during chemotaxis rather than a core compartment. Supporting Evidence: PMID:12821670 PAR-2/beta-arrestin/ERK1/2 scaffolding complex is enriched in the pseudopodia
GO:0005634 nucleus	IDA PMID:11254359 Pecam-1 is a modulator of stat family member phosphorylation...	ACCEPT	Summary: nucleus is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005634 nucleus	IDA PMID:11726647 Prolonged nuclear retention of activated extracellular signa...	ACCEPT	Summary: nucleus is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0005737 cytoplasm	IDA PMID:11726647 Prolonged nuclear retention of activated extracellular signa...	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0004707 MAP kinase activity	IDA PMID:15314156 MUC20 suppresses the hepatocyte growth factor-induced Grb2-R...	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0051216 cartilage development	IDA PMID:17644814 Cytokine-like 1 (Cytl1) regulates the chondrogenesis of mese...	KEEP AS NON CORE	Summary: Cartilage development annotation from the Cytl1 chondrogenesis study. Reason: The cached abstract describes Cytl1-driven chondrogenesis without detailing the ERK assays, which are in the full text the curator used; ERK1/2 signaling in chondrogenic differentiation is well established (compare the FGFR3 bone study PMID:20053668), so the row is retained as a non-core skeletal-development role.
GO:0031663 lipopolysaccharide-mediated signaling pathway	IDA PMID:12872135 Identification of Lps2 as a key transducer of MyD88-independ...	KEEP AS NON CORE	Summary: LPS-mediated signaling annotation from the Trif(Lps2) identification study. Reason: The paper defines Trif-dependent TLR4 signaling in mouse; ERK1 activation is part of the macrophage LPS response assayed in the full text, and MAPK activation downstream of TLR4 is core innate-immunity biology, so this pathway-context row is kept non-core.
GO:0032496 response to lipopolysaccharide	IDA PMID:12872135 Identification of Lps2 as a key transducer of MyD88-independ...	KEEP AS NON CORE	Summary: response to lipopolysaccharide sits alongside the LPS pathway row from the same study. Reason: Adjudicated with its sibling annotation from PMID:12872135; ERK1 phosphorylation is a standard readout of the mouse macrophage LPS response, a stimulus-context annotation rather than a core function.
GO:0043330 response to exogenous dsRNA	IDA PMID:12872135 Identification of Lps2 as a key transducer of MyD88-independ...	KEEP AS NON CORE	Summary: ERK1 participates in macrophage responses to dsRNA downstream of TLR3/Trif. Reason: The cached abstract of the Trif(Lps2) study covers cytokine responses to double-stranded RNA; the ERK1-specific assay is in the full text the curator read, and ERK activation downstream of TLR3 engagement is standard innate-immune signaling, so the annotation is retained as a non-core immune output.
GO:0019233 sensory perception of pain	IMP PMID:11356865 Metabotropic glutamate receptor subtypes 1 and 5 are activat...	KEEP AS NON CORE	Summary: Spinal ERK1/2 activation downstream of group I mGluRs drives inflammatory pain sensitivity. Reason: The study shows mGluR1/5 activation engages ERK1 and ERK2 in dorsal horn neurons and that this signaling underlies nociceptive plasticity, supporting a pain-modulation role; a systems-level behavioral output, hence non-core. Supporting Evidence: PMID:11356865 activation of these group I mGluRs leads to activation of ERK1 and ERK2, resulting in enhanced pain sensitivity
GO:0004672 protein kinase activity	IDA PMID:15383658 p53-dependent inhibition of FKHRL1 in response to DNA damage...	MODIFY	Summary: protein kinase activity is less specific than ERK MAP kinase activity. Reason: MAPK1/MAPK3 are ERK-family MAP kinases with proline-directed serine/threonine protein kinase activity. Proposed replacements: MAP kinase activity Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0006468 protein phosphorylation	IDA PMID:15383658 p53-dependent inhibition of FKHRL1 in response to DNA damage...	ACCEPT	Summary: protein phosphorylation is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0006974 DNA damage response	IDA PMID:15383658 p53-dependent inhibition of FKHRL1 in response to DNA damage...	KEEP AS NON CORE	Summary: ERK1/2 mediate p53-dependent SGK1 induction after DNA damage. Reason: DNA damage-induced SGK1 up-regulation, required for FOXO3a inhibition, occurs through ERK1/2-mediated posttranslational regulation, placing ERK1 within a DNA damage signaling circuit; a stress-context role, retained as non-core. Supporting Evidence: PMID:15383658 this induction was through extracellular signal-regulated kinase 1/2-mediated posttranslational regulation
GO:0004707 MAP kinase activity	IMP PMID:11841548 Role of the nude gene in epithelial terminal differentiation...	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0006468 protein phosphorylation	IDA PMID:11841548 Role of the nude gene in epithelial terminal differentiation...	ACCEPT	Summary: protein phosphorylation is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0005515 protein binding	IPI PMID:15544353 Treatment of cells with the angiogenic inhibitor fumagillin ...	MARK AS OVER ANNOTATED	Summary: protein binding records a physical association but is too generic to describe the gene product function. Reason: The evidence supports regulated signaling-complex assembly, not a meaningful standalone protein binding function; more informative molecular and pathway terms capture the biology. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0001784 phosphotyrosine residue binding	IMP PMID:14636584 Phosphorylation-dependent paxillin-ERK association mediates ...	KEEP AS NON CORE	Summary: phosphotyrosine residue binding is supported in a specific HGF/paxillin cell-matrix interaction context, but is not the core ERK1 kinase function. Reason: The cited evidence supports a context-specific tyrosine-phosphorylation-dependent ERK association. Supporting Evidence: PMID:14636584 this is mediated by the tyrosine phosphorylation-dependent association of inactive ERK and the focal adhesion complex protein paxillin
GO:0005737 cytoplasm	IDA PMID:12223545 Copper/zinc superoxide dismutase attenuates neuronal cell de...	ACCEPT	Summary: cytoplasm is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are described as present in cytoplasmic, nuclear, and membrane-associated pools.
GO:0016310 phosphorylation	TAS PMID:12223545 Copper/zinc superoxide dismutase attenuates neuronal cell de...	MODIFY	Summary: Phosphorylation is too broad for an ERK kinase annotation. Reason: The relevant process is protein phosphorylation catalyzed by ERK MAP kinase activity. Proposed replacements: protein phosphorylation Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0004707 MAP kinase activity	TAS PMID:11684667 Erk MAP kinase regulates branching morphogenesis in the deve...	ACCEPT	Summary: MAP kinase activity is consistent with core ERK MAP kinase activity, phosphorylation, cascade function, or localization. Reason: This term directly captures ERK catalytic activity, ERK cascade participation, protein phosphorylation, or canonical nucleo-cytoplasmic localization. Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 are proline-directed Ser/Thr protein kinases, with strong preference for PX(S/T)P motifs
GO:0007165 signal transduction	TAS PMID:11684667 Erk MAP kinase regulates branching morphogenesis in the deve...	MODIFY	Summary: signal transduction is a broad parent for ERK1/2 signaling. Reason: The more specific biological process for these ERK proteins is the ERK1 and ERK2 cascade. Proposed replacements: ERK1 and ERK2 cascade Supporting Evidence: file:mouse/Mapk3/Mapk3-deep-research-falcon.md ERK1/2 function as the final kinases in the RAS-RAF-MEK-ERK cascade
GO:0009887 animal organ morphogenesis	IDA PMID:11684667 Erk MAP kinase regulates branching morphogenesis in the deve...	MODIFY	Summary: Animal organ morphogenesis is far broader than the actual finding, which is that Erk MAP kinase activity is required for branching morphogenesis of the ureteric bud in kidney development. Reason: The experiment specifically shows MEK-inhibitor-sensitive, Erk-dependent ureteric bud branching; the generic organ morphogenesis term should be narrowed to the branching-specific term that matches the assay. PD98059 inhibits MEK, so the assay cannot distinguish ERK1 from ERK2 - the identical row on the ERK2 paralog Mapk1 is narrowed the same way. Proposed replacements: branching involved in ureteric bud morphogenesis Supporting Evidence: PMID:11684667 MAP kinase is therefore essential for normal branching morphogenesis of the ureteric bud

Gene Description

Existing Annotations Review

Core Functions

ERK1 catalyzes proline-directed phosphorylation of protein substrates at serine/threonine residues after MEK-mediated dual activation-loop phosphorylation.

Acts with ERK2 as the final kinase tier of the RAS-RAF-MEK-ERK cascade, with output shaped by localization, docking motifs, and signal duration.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

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