id: P63086
gene_symbol: Mapk1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:10116
  label: Rattus norvegicus
description: >-
  Mapk1 (also known as Erk2, Prkm1, p42-MAPK) encodes ERK2, the rat ortholog of
  the extracellular signal-regulated kinase 2. It is a proline-directed
  serine/threonine protein kinase (EC 2.7.11.24) of the CMGC group and the
  terminal effector kinase of the canonical RAS-RAF-MEK-ERK (ERK1/2) MAPK
  cascade. ERK2 is activated by dual phosphorylation on the TEY activation-loop
  motif (Thr183/Tyr185 in rat numbering, equivalent to the TEY threonine/tyrosine
  pair) by the upstream MAP2Ks MEK1/MEK2 (MAP2K1/MAP2K2), downstream of receptor
  tyrosine kinases (EGFR and other growth factor receptors), G-protein-coupled
  receptors, and other stimuli that activate RAS. Once activated, ERK2
  phosphorylates a Ser/Thr-Pro consensus motif on hundreds of cytoplasmic and
  nuclear substrates (e.g., RSK kinases, ELK1 and other transcription factors,
  translation-control nodes, cytoskeletal and membrane scaffold proteins such as
  NHE1/SLC9A1). Its core molecular function is protein serine/threonine (MAP)
  kinase activity using ATP, and its core biological role is transduction of the
  ERK1/2 MAPK cascade. Subcellular localization (cytoplasm versus nucleus) is a
  key regulatory feature: activated ERK2 translocates to the nucleus to drive
  transcriptional programs, and is sequestered/exported by binding partners such
  as PEA-15. Because ERK2 is an extremely pleiotropic signaling hub, it is
  annotated to a very large number of downstream and developmental processes;
  most of these are context-specific consequences of cascade activity rather
  than the core function of the protein.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Activated ERK2 translocates to the nucleus where it phosphorylates
      transcription factors; nuclear localization is well established and a core
      site of action.
    action: ACCEPT
    reason: Core localization. Activated ERK2 accumulates in the nucleus to drive
      transcription; supported by the phylogenetic inference and by direct
      evidence in this review.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        transcriptional outcomes often requiring nuclear ERK
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ERK2 resides in the cytoplasm in the basal state and is activated there
      by the cytoplasmic MEK1/2; cytoplasmic localization is a core feature.
    action: ACCEPT
    reason: Core localization. ERK2 is cytoplasmic in resting cells and is subject
      to cytoplasmic sequestration; this is the compartment of initial activation.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        NHE1/Slc9a1** can act as a **membrane scaffold** for ERK2
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ERK2 is a central intracellular signal-transducing kinase. This is a
      generic parent of the more specific ERK1/2 cascade terms.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic. The more specific GO:0070371 (ERK1 and ERK2 cascade)
      better captures the core biological process; this broad parent is retained as
      non-core.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ERK2 is a proline-directed serine/threonine protein kinase. This is a
      core molecular function (parent of MAP kinase activity).
    action: ACCEPT
    reason: Core molecular function. ERK2 phosphorylates Ser/Thr-Pro motifs on
      substrates; well supported phylogenetically and experimentally.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        ERK family proteins are annotated under a **serine/threonine kinase domain category**
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ERK2 acts downstream of cell-surface receptors (RTKs, GPCRs), but this
      broad term is a generic parent of the specific cascade/receptor pathways.
    action: KEEP_AS_NON_CORE
    reason: Generic parent. The specific receptor pathways and the ERK1/2 cascade
      term capture this better; kept as non-core context.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Generic parent of protein serine/threonine kinase / MAP kinase activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general. The specific MF terms (MAP kinase activity, protein
      serine/threonine kinase activity) are present and preferred.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ERK2 IS a MAP kinase; this is the most specific and accurate molecular
      function term for this protein.
    action: ACCEPT
    reason: Core molecular function. ERK2 is the canonical MAP kinase; this term is
      the precise MF.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        Mapk1 encodes ERK2**, a serine/threonine MAP kinase in the canonical RAS→RAF→MEK→ERK cascade
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: ERK2 binds ATP in its kinase domain and transfers the gamma-phosphate to
      substrates; a core molecular function of the enzyme.
    action: ACCEPT
    reason: Core molecular function. ATP binding is required for the phosphotransfer
      reaction; experimentally demonstrated (PMID:15027896) and assay-confirmed in
      the deep research.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        an in vitro kinase assay with active TEY-phosphorylated ERK2 and an ATPγS analog
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Nuclear localization (duplicate of the IBA nucleus annotation).
    action: ACCEPT
    reason: Core localization, consistent with the IBA annotation and direct evidence.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Nucleoplasm is a more specific child of nucleus; ERK2 acts within the
      nucleoplasm on transcription factors.
    action: ACCEPT
    reason: Consistent specific nuclear localization; supported by IDA evidence
      (PMID:7889942) elsewhere in this review.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoplasmic localization (duplicate of the IBA cytoplasm annotation).
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK signaling can be organized on endosomal compartments, but early
      endosome is a minor/context-specific localization, not a core site.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization tied to endosomal signaling scaffolds;
      not a core compartment for ERK2 function.
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Context-specific endosomal localization (see early endosome).
    action: KEEP_AS_NON_CORE
    reason: Minor/context-specific localization, not core.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Golgi-localized ERK pools exist and ERK can regulate Golgi dynamics, but
      this is a specialized localization rather than the core site of action.
    action: KEEP_AS_NON_CORE
    reason: Specialized localized signaling pool; non-core.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Centrosomal localization is reported in mitotic contexts; specialized,
      not core.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization (mitosis); non-core.
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Spindle localization in mitosis is a specialized, context-specific site.
    action: KEEP_AS_NON_CORE
    reason: Context-specific mitotic localization; non-core.
- term:
    id: GO:0005901
    label: caveola
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: ERK can be recruited to caveolae (e.g., via MURC/Cavin-4) in specialized
      signaling, supported by IDA (PMID:24567387); specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific membrane microdomain localization; non-core but
      experimentally supported.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ERK localizes to focal adhesions in migration contexts; specialized
      localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization linked to cell migration; non-core.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Nuclear ERK2 regulates Pol II transcription by phosphorylating
      transcription factors (e.g., ELK1). This is a downstream consequence of cascade
      activity rather than the core function.
    action: KEEP_AS_NON_CORE
    reason: Genuine but downstream/indirect process; ERK2 regulates transcription via
      substrate phosphorylation. Kept as non-core.
- term:
    id: GO:0032872
    label: regulation of stress-activated MAPK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK2 can cross-regulate stress-activated MAPK (p38/JNK) cascades, but
      this is a secondary crosstalk role, not core.
    action: KEEP_AS_NON_CORE
    reason: Crosstalk/regulatory role; non-core relative to the ERK1/2 cascade itself.
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK activation downstream of nicotinic receptors is a stimulus-specific
      response, not a core function.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (also supported by IGI PMID:11404397); non-core.
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK2 promotes translation via downstream nodes (e.g., RSK/MNK, eIF4E
      pathway, EIF4EBP1, EEF2K). This is a downstream consequence of cascade activity.
    action: KEEP_AS_NON_CORE
    reason: Downstream regulatory consequence (also IMP PMID:15027896); non-core.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        ERK2 is also linked to translation-control nodes including Eif4ebp1 and Eef2k
- term:
    id: GO:0046697
    label: decidualization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Decidualization is a tissue-specific developmental process downstream of
      MAPK activation; not a core ERK2 function.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental process (also IDA PMID:21248290); non-core.
- term:
    id: GO:0051493
    label: regulation of cytoskeleton organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK2 phosphorylates cytoskeletal regulators, influencing cytoskeleton
      organization; a downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Downstream effector consequence; non-core.
- term:
    id: GO:0070371
    label: ERK1 and ERK2 cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This is the defining biological process for ERK2 - it IS one of the two
      terminal kinases of the ERK1/2 cascade. Core BP.
    action: ACCEPT
    reason: Core biological process. ERK2 is a defining component of the ERK1 and
      ERK2 cascade.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        ERK1/2 (MAPK3/MAPK1) are described as **terminal kinases** in the canonical **RAS→RAF→MEK→ERK** cascade
- term:
    id: GO:0071375
    label: cellular response to peptide hormone stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK activation downstream of peptide hormones is a stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0071396
    label: cellular response to lipid
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Stimulus-specific cellular response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0072584
    label: caveolin-mediated endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: A specialized endocytosis process where ERK has been implicated;
      downstream/context-specific.
    action: KEEP_AS_NON_CORE
    reason: Context-specific process; non-core.
- term:
    id: GO:0090170
    label: regulation of Golgi inheritance
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: ERK2 has been implicated in mitotic Golgi partitioning; specialized
      downstream process.
    action: KEEP_AS_NON_CORE
    reason: Specialized mitotic process; non-core.
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: ERK2 phosphorylates serine residues; a more specific child of protein
      serine/threonine kinase activity. Accurate.
    action: ACCEPT
    reason: Accurate specific MF; ERK2 is a Ser/Thr (proline-directed) kinase.
- term:
    id: GO:2000641
    label: regulation of early endosome to late endosome transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Specialized endosomal trafficking process linked to ERK; downstream.
    action: KEEP_AS_NON_CORE
    reason: Context-specific process; non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21070949
  review:
    summary: This IPI annotation reflects the ERK2-DCC docking interaction (ERK2
      phosphorylates DCC via direct docking). The generic protein binding term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The protein binding term is non-informative per curation guidelines. The
      underlying interaction (DCC docking/substrate) is better captured by the kinase
      activity and substrate-docking functions.
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IMP
  original_reference_id: PMID:29959233
  review:
    summary: ERK2 serine kinase activity demonstrated in the context of Ras/MAPK
      regulation of connexin-43/gap junctions. Accurate MF.
    action: ACCEPT
    reason: Accurate specific molecular function with experimental support.
    supported_by:
    - reference_id: PMID:29959233
      supporting_text: increased phosphorylation of S279/282 of Cx43, which signals
        clathrin-mediated internalization and subsequent lysosomal degradation of
        Cx43
- term:
    id: GO:0045880
    label: positive regulation of smoothened signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Crosstalk between ERK and Hedgehog/Smoothened signaling is reported but
      indirect; not a core ERK2 function and based on sequence-similarity transfer.
    action: KEEP_AS_NON_CORE
    reason: Indirect crosstalk role from ISS transfer; non-core.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Refers to ERK2 homodimerization. While ERK2 can dimerize, this is a
      relatively uninformative interaction term.
    action: KEEP_AS_NON_CORE
    reason: ERK2 homodimerization is documented but its functional relevance is
      debated; retained as non-core rather than core function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Nucleoplasm localization (ISO duplicate). Consistent.
    action: ACCEPT
    reason: Consistent specific nuclear localization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Cytosolic localization; consistent with cytoplasmic localization and the
      site of basal ERK2 and MEK-mediated activation.
    action: ACCEPT
    reason: Core localization (cytosolic pool), consistent with TAS and other
      evidence.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        NHE1/Slc9a1** can act as a **membrane scaffold** for ERK2
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: IDA
  original_reference_id: PMID:7889942
  review:
    summary: Direct demonstration of ERK MAP kinase activity (Elk-1 phosphorylation /
      ternary complex). Core MF with strong experimental support.
    action: ACCEPT
    reason: Core molecular function with direct experimental evidence.
- term:
    id: GO:0150078
    label: positive regulation of neuroinflammatory response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: A tissue/context-specific downstream process inferred by orthology; not a
      core ERK2 function.
    action: KEEP_AS_NON_CORE
    reason: Context-specific downstream process from ISO transfer; non-core.
- term:
    id: GO:0061514
    label: interleukin-34-mediated signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK acts downstream of IL-34/CSF1R signaling; a stimulus-specific pathway
      inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific signaling context; non-core.
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is a core component of the MAPK cascade; this is the generic parent
      of the ERK1/2 cascade term.
    action: ACCEPT
    reason: Core biological process (generic parent of ERK1/2 cascade). ERK2 is a
      terminal MAPK of this cascade.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        concludes that EGF activates the canonical MAPK pathway in this native rat tissue context
- term:
    id: GO:0007173
    label: epidermal growth factor receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is a key effector of EGFR signaling; this is a major upstream
      pathway that activates the ERK1/2 cascade. Well supported in rat tissue.
    action: KEEP_AS_NON_CORE
    reason: Genuine and important upstream-receptor pathway, but it is the receptor
      context that activates ERK2 rather than ERK2's own core function. Kept as
      non-core; strongly corroborated by rat IMCD EGF data.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        pathway enrichment confirms engagement of **RAF–MEK–ERK signaling**
- term:
    id: GO:0032206
    label: positive regulation of telomere maintenance
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Downstream/indirect process inferred by orthology; not a core function.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream process; non-core.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: MAP kinase activity (ISO duplicate). Core MF.
    action: ACCEPT
    reason: Core molecular function (orthology-inferred duplicate of the IDA/IEA MAP
      kinase activity annotations).
- term:
    id: GO:0045542
    label: positive regulation of cholesterol biosynthetic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Indirect downstream metabolic process inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream process; non-core.
- term:
    id: GO:0061431
    label: cellular response to methionine
  evidence_type: IEP
  original_reference_id: PMID:22676582
  review:
    summary: ERK activation under methionine starvation (Nrf2/GST context); a
      stimulus-specific cellular response inferred from expression/phenotype.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0071380
    label: cellular response to prostaglandin E stimulus
  evidence_type: IEP
  original_reference_id: PMID:11875501
  review:
    summary: ERK activation downstream of PGE2/EGFR transactivation; stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: IEP
  original_reference_id: PMID:8223435
  review:
    summary: cAMP modulates ERK2 activation (cAMP antagonizes Ras-directed ERK2
      activation); stimulus-specific response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response/crosstalk (IEP); non-core.
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEP
  original_reference_id: PMID:7478291
  review:
    summary: ERK2 detected in postsynaptic density fractions from rat brain; a
      neuronal localization. Specialized.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific neuronal localization; non-core but experimentally
      observed in rat brain.
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IDA
  original_reference_id: PMID:7478291
  review:
    summary: Direct observation of ERK2 in postsynaptic density fractions (rat brain).
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific neuronal localization with direct evidence; non-core.
- term:
    id: GO:0032355
    label: response to estradiol
  evidence_type: IEP
  original_reference_id: PMID:15893655
  review:
    summary: Estradiol rapidly enhances ERK2 phosphorylation in rat brain;
      stimulus-specific response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0036120
    label: cellular response to platelet-derived growth factor stimulus
  evidence_type: IEP
  original_reference_id: PMID:8246947
  review:
    summary: ERK2 is activated downstream of PDGF; a growth-factor-specific response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0071364
    label: cellular response to epidermal growth factor stimulus
  evidence_type: IEP
  original_reference_id: PMID:8246947
  review:
    summary: ERK2 is activated downstream of EGF; well supported in rat tissue
      (IMCD EGF phosphoproteomics shows TEY phosphorylation of Mapk1). Stimulus
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response, but strongly corroborated; non-core relative
      to the cascade itself.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        Dual phosphorylation in the TEY activation segment region** is directly observed for rat Mapk1/ERK2
- term:
    id: GO:0033574
    label: response to testosterone
  evidence_type: IEP
  original_reference_id: PMID:22265242
  review:
    summary: ERK2 in dentate gyrus mediates antidepressant effects of testosterone;
      stimulus-specific.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0044849
    label: estrous cycle
  evidence_type: IEP
  original_reference_id: PMID:22521590
  review:
    summary: ERK2 expression correlates with estrous-cycle-related behavior; an
      organism-level physiological context, not a molecular role.
    action: KEEP_AS_NON_CORE
    reason: Physiological/behavioral context (IEP); non-core.
- term:
    id: GO:0042220
    label: response to cocaine
  evidence_type: IEP
  original_reference_id: PMID:19457111
  review:
    summary: ERK signaling adaptations in cocaine sensitization; stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0042542
    label: response to hydrogen peroxide
  evidence_type: IEP
  original_reference_id: PMID:11679970
  review:
    summary: ERK2 signaling altered by oxidative stress; stimulus-specific response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0097305
    label: response to alcohol
  evidence_type: IEP
  original_reference_id: PMID:21790671
  review:
    summary: ERK1/2 activation accompanies alcohol-induced liver injury;
      stimulus-specific response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:1990314
    label: cellular response to insulin-like growth factor stimulus
  evidence_type: IEP
  original_reference_id: PMID:9235900
  review:
    summary: IGF-I rapidly activates ERK2 in cardiac myocytes; growth-factor-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IEP); non-core.
- term:
    id: GO:0048009
    label: insulin-like growth factor receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector of IGF-1R signaling; an upstream receptor pathway
      context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Upstream-receptor pathway context; non-core.
- term:
    id: GO:0008286
    label: insulin receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector of insulin receptor signaling; upstream pathway
      context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Upstream-receptor pathway context; non-core.
- term:
    id: GO:0014044
    label: Schwann cell development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: A developmental process where ERK signaling is required; tissue/lineage
      specific, downstream of the cascade.
    action: KEEP_AS_NON_CORE
    reason: Developmental process inferred by orthology; non-core.
- term:
    id: GO:0042552
    label: myelination
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process where ERK signaling participates; downstream and
      tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Developmental process inferred by orthology; non-core.
- term:
    id: GO:0038133
    label: ERBB2-ERBB3 signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector of ERBB2-ERBB3 signaling; upstream receptor pathway
      context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Upstream-receptor pathway context; non-core.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Nuclear localization (ISO duplicate). Consistent core localization.
    action: ACCEPT
    reason: Core localization, consistent with other nucleus annotations.
- term:
    id: GO:0010759
    label: positive regulation of macrophage chemotaxis
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: A cell-type-specific downstream process inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific downstream process; non-core.
- term:
    id: GO:0120041
    label: positive regulation of macrophage proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: A cell-type-specific downstream process inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific downstream process; non-core.
- term:
    id: GO:0042307
    label: positive regulation of protein import into nucleus
  evidence_type: IMP
  original_reference_id: PMID:19524539
  review:
    summary: From the LysRS/Ap4A study; ERK2 phosphorylation of LysRS affecting its
      nuclear function. A specific downstream regulatory effect.
    action: KEEP_AS_NON_CORE
    reason: Specific downstream regulatory effect (IMP); non-core.
- term:
    id: GO:0060045
    label: positive regulation of cardiac muscle cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:26884868
  review:
    summary: MAPK1 promotes cardiomyocyte proliferation via MALAT1/PI3K-AKT; a
      cell-type-specific downstream process.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific downstream process (IMP); non-core.
- term:
    id: GO:0003690
    label: double-stranded DNA binding
  evidence_type: IDA
  original_reference_id: PMID:26950759
  review:
    summary: The cited study shows that ERK2 activation-loop phosphorylation/mutation
      alters oligonucleotide binding; ERK2 can bind DNA. This is an unusual,
      non-catalytic moonlighting activity, not the core kinase function.
    action: KEEP_AS_NON_CORE
    reason: Experimentally observed but non-canonical moonlighting DNA-binding
      activity; not the core kinase function. Retained as non-core.
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:26950759
  review:
    summary: Generic protein phosphorylation; the catalytic output of ERK2 kinase
      activity. Accurate but generic relative to the MF terms.
    action: KEEP_AS_NON_CORE
    reason: Generic BP that is the direct output of the kinase activity; the MF terms
      (MAP kinase activity) capture this more precisely. Non-core.
- term:
    id: GO:0046697
    label: decidualization
  evidence_type: IDA
  original_reference_id: PMID:21248290
  review:
    summary: MAPK activation in regional decidualization in rats; tissue-specific
      developmental process.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific developmental process; non-core.
- term:
    id: GO:0019902
    label: phosphatase binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 binds dual-specificity phosphatases (DUSPs/MKPs) that dephosphorylate
      it; a genuine regulatory interaction but not a core function.
    action: KEEP_AS_NON_CORE
    reason: Regulatory protein interaction (with MKPs); non-core, more informative
      than generic protein binding.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Protein serine/threonine kinase activity (ISO duplicate). Core MF.
    action: ACCEPT
    reason: Core molecular function (orthology-inferred duplicate).
- term:
    id: GO:0071356
    label: cellular response to tumor necrosis factor
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Stimulus-specific cellular response inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0030641
    label: regulation of cellular pH
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Reflects ERK2 phosphorylation of the NHE1/SLC9A1 Na+/H+ exchanger;
      a specific downstream effect, corroborated in rat IMCD (ERK2 phosphorylates
      NHE1 at Ser727/Ser730).
    action: KEEP_AS_NON_CORE
    reason: Specific downstream effector consequence (NHE1 phosphorylation); non-core
      but corroborated.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        NHE1/Slc9a1** can act as a **membrane scaffold** for ERK2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24567387
  review:
    summary: ERK interaction with MURC/Cavin-4 (caveolar recruitment). The generic
      protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The protein binding term is non-informative per curation guidelines; the
      caveolar localization is captured by the caveola term.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:24567387
  review:
    summary: Cytoplasmic localization with direct evidence. Core localization.
    action: ACCEPT
    reason: Core localization with direct experimental support.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:24567387
  review:
    summary: ERK recruited to plasma membrane/caveolae in cardiac hypertrophy context;
      a specialized localized pool.
    action: KEEP_AS_NON_CORE
    reason: Context-specific membrane recruitment; non-core.
- term:
    id: GO:0005901
    label: caveola
  evidence_type: IDA
  original_reference_id: PMID:24567387
  review:
    summary: Direct evidence of ERK recruitment to caveolae via MURC/Cavin-4.
      Specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific membrane microdomain localization with direct evidence;
      non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12944431
  review:
    summary: DOC1R interaction (a MAP kinase substrate in oocytes). The generic
      protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The protein binding term is non-informative; the substrate relationship is
      captured by kinase activity.
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Stimulus-specific response (ISO duplicate of the nicotine annotations).
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0035094
    label: response to nicotine
  evidence_type: IGI
  original_reference_id: PMID:11404397
  review:
    summary: Beta-amyloid activates MAPK cascade via alpha7 nicotinic receptors;
      stimulus-specific response with genetic-interaction evidence.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response (IGI); non-core.
- term:
    id: GO:0034198
    label: cellular response to amino acid starvation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Stimulus-specific cellular response inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0051403
    label: stress-activated MAPK cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is not part of the stress-activated (p38/JNK) MAPK cascade itself;
      this annotation conflates the ERK cascade with stress-activated cascades.
    action: MARK_AS_OVER_ANNOTATED
    reason: ERK2 is the terminal kinase of the ERK1/2 (mitogen-activated) cascade, not
      a component of the stress-activated (p38/JNK) cascade. This orthology-inferred
      term likely over-annotates; ERK2's relationship to stress cascades is regulatory
      crosstalk (captured by GO:0032872), not membership.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: IMP
  original_reference_id: PMID:19524539
  review:
    summary: MAP kinase activity demonstrated via LysRS phosphorylation. Core MF.
    action: ACCEPT
    reason: Core molecular function with experimental support.
- term:
    id: GO:0015966
    label: diadenosine tetraphosphate biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:19524539
  review:
    summary: ERK2 phosphorylation of LysRS triggers Ap4A production in immune
      signaling; an indirect downstream consequence, not an ERK2 enzymatic activity.
    action: KEEP_AS_NON_CORE
    reason: Indirect downstream consequence via substrate (LysRS); ERK2 does not
      itself synthesize Ap4A. Non-core.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:19524539
  review:
    summary: ERK2 promotes transcription via substrate phosphorylation; downstream
      regulatory consequence.
    action: KEEP_AS_NON_CORE
    reason: Downstream transcriptional regulation via substrates; non-core.
- term:
    id: GO:0070371
    label: ERK1 and ERK2 cascade
  evidence_type: IMP
  original_reference_id: PMID:19524539
  review:
    summary: ERK1/2 cascade (IMP). Core biological process.
    action: ACCEPT
    reason: Core biological process with experimental support.
- term:
    id: GO:0030278
    label: regulation of ossification
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process where ERK signaling participates; tissue-specific,
      downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process inferred by orthology; non-core.
- term:
    id: GO:0007507
    label: heart development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK1/2 signaling is required for heart development; a pleiotropic
      developmental process downstream of the cascade.
    action: KEEP_AS_NON_CORE
    reason: Developmental process inferred by orthology; non-core.
- term:
    id: GO:0014032
    label: neural crest cell development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process where ERK signaling participates; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process inferred by orthology; non-core.
- term:
    id: GO:0030878
    label: thyroid gland development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0042473
    label: outer ear morphogenesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology (RASopathy-related); downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0048538
    label: thymus development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0060324
    label: face development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology (RASopathy-related); downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0061308
    label: cardiac neural crest cell development involved in heart development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0060020
    label: Bergmann glial cell differentiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Cell-type-specific developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0070371
    label: ERK1 and ERK2 cascade
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK1/2 cascade (ISO duplicate). Core biological process.
    action: ACCEPT
    reason: Core biological process (orthology-inferred duplicate).
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Generic protein phosphorylation (the catalytic output). Generic relative
      to the MF terms.
    action: KEEP_AS_NON_CORE
    reason: Generic BP output of kinase activity; non-core.
- term:
    id: GO:0060425
    label: lung morphogenesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0060440
    label: trachea formation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0060291
    label: long-term synaptic potentiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK signaling contributes to LTP; a neuronal physiological process
      downstream of the cascade.
    action: KEEP_AS_NON_CORE
    reason: Neuronal physiological process inferred by orthology; non-core.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cytoplasmic localization (ISS duplicate). Core localization.
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0072686
    label: mitotic spindle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Mitotic spindle localization (specific child of spindle). Specialized
      mitotic localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific mitotic localization; non-core.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: IMP
  original_reference_id: PMID:16955078
  review:
    summary: MAP kinase activity (mTOR signaling/TBI context). Core MF.
    action: ACCEPT
    reason: Core molecular function with experimental support.
- term:
    id: GO:0018105
    label: peptidyl-serine phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:16955078
  review:
    summary: ERK2 phosphorylates serine residues on substrates; a specific child of
      protein phosphorylation describing the catalytic output.
    action: KEEP_AS_NON_CORE
    reason: Describes the catalytic output (serine phosphorylation); the MF terms
      capture this more precisely. Non-core.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:16943189
  review:
    summary: ERK2 binds upstream/partner kinases (e.g., TAB1 context); a more
      informative interaction term than generic protein binding.
    action: KEEP_AS_NON_CORE
    reason: Informative protein-interaction term reflecting ERK2 binding to kinases in
      its signaling module; non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-3245934
  review:
    summary: Nucleoplasm localization, from a Reactome reaction (Mapk1 phosphorylates
      ERF). Consistent core nuclear localization.
    action: ACCEPT
    reason: Consistent specific nuclear localization (TAS from Reactome).
- term:
    id: GO:0038127
    label: ERBB signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector of ERBB receptor signaling; upstream pathway context
      inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Upstream-receptor pathway context; non-core.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Cytoplasmic localization (ISO duplicate). Core localization.
    action: ACCEPT
    reason: Core localization.
- term:
    id: GO:0070849
    label: response to epidermal growth factor
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ERK2 responds to EGF; strongly supported in rat tissue (IMCD EGF
      phosphoproteomics). Stimulus response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core but well corroborated.
    supported_by:
    - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
      supporting_text: |-
        concludes that EGF activates the canonical MAPK pathway in this native rat tissue context
- term:
    id: GO:0070849
    label: response to epidermal growth factor
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Response to EGF (ISO duplicate). Stimulus response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0018105
    label: peptidyl-serine phosphorylation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Serine phosphorylation output (ISO duplicate). Generic catalytic output.
    action: KEEP_AS_NON_CORE
    reason: Describes the catalytic output; non-core relative to MF terms.
- term:
    id: GO:0018105
    label: peptidyl-serine phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:7768935
  review:
    summary: Direct demonstration of ERK2 serine phosphorylation of tristetraprolin
      in vitro. Catalytic output.
    action: KEEP_AS_NON_CORE
    reason: Direct evidence for the catalytic output (serine phosphorylation); the MF
      terms capture this more precisely. Non-core.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Nuclear localization from a review of ERK signaling across compartments.
      Core localization.
    action: ACCEPT
    reason: Core localization (TAS).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: A mitochondrial ERK pool is reported; a minor specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Minor/specialized localization; non-core.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Endosomal ERK signaling pool; context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization; non-core.
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Endosomal ERK signaling pool; context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization; non-core.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Golgi-associated ERK pool; specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Specialized localization; non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Cytosolic localization. Core localization (the basal pool).
    action: ACCEPT
    reason: Core localization (cytosolic pool, TAS).
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: ERK associates with cytoskeletal structures in some contexts; specialized
      localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization; non-core.
- term:
    id: GO:0005901
    label: caveola
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Caveolar ERK pool; specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Specialized localization; non-core.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Focal-adhesion-associated ERK pool; specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Specialized localization; non-core.
- term:
    id: GO:0032872
    label: regulation of stress-activated MAPK cascade
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: ERK crosstalk regulating stress-activated MAPK cascades; secondary
      regulatory role.
    action: KEEP_AS_NON_CORE
    reason: Crosstalk/regulatory role; non-core.
- term:
    id: GO:0051493
    label: regulation of cytoskeleton organization
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: ERK phosphorylation of cytoskeletal regulators; downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Downstream effector consequence; non-core.
- term:
    id: GO:0072584
    label: caveolin-mediated endocytosis
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Specialized endocytic process where ERK is implicated; downstream.
    action: KEEP_AS_NON_CORE
    reason: Context-specific process; non-core.
- term:
    id: GO:0090170
    label: regulation of Golgi inheritance
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: ERK role in mitotic Golgi partitioning; specialized process.
    action: KEEP_AS_NON_CORE
    reason: Specialized mitotic process; non-core.
- term:
    id: GO:2000641
    label: regulation of early endosome to late endosome transport
  evidence_type: TAS
  original_reference_id: PMID:19565474
  review:
    summary: Specialized endosomal trafficking process linked to ERK; downstream.
    action: KEEP_AS_NON_CORE
    reason: Context-specific process; non-core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19200235
  review:
    summary: Generic protein binding from a dopamine/ERK apoptosis study;
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The protein binding term is non-informative per curation guidelines.
- term:
    id: GO:0010800
    label: positive regulation of peptidyl-threonine phosphorylation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: A downstream regulatory consequence (promoting threonine phosphorylation
      of targets) inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Downstream regulatory consequence; non-core.
- term:
    id: GO:0031143
    label: pseudopodium
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Pseudopodium localization inferred by orthology (migration context);
      specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Context-specific localization; non-core.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Mitochondrial ERK pool (ISO duplicate); minor specialized localization.
    action: KEEP_AS_NON_CORE
    reason: Minor/specialized localization; non-core.
- term:
    id: GO:0033598
    label: mammary gland epithelial cell proliferation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Cell-type-specific downstream proliferation process inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific downstream process; non-core.
- term:
    id: GO:0008353
    label: RNA polymerase II CTD heptapeptide repeat kinase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: This term implies ERK2 phosphorylates the Pol II CTD as a CTD kinase. ERK2
      is a proline-directed kinase and can phosphorylate Ser-Pro sites including in the
      CTD, but assigning a dedicated CTD-kinase MF (typically reserved for CDKs) is
      likely an over-annotation by orthology transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: ERK2's role as a bona fide Pol II CTD kinase is not its established core
      function; this orthology-inferred specific MF over-annotates the protein. The
      canonical CTD kinases are CDK7/CDK9/CDK12. Marked as over-annotated.
- term:
    id: GO:0009636
    label: response to toxic substance
  evidence_type: IDA
  original_reference_id: PMID:17651772
  review:
    summary: ERK activation in kidney upon ochratoxin A exposure; stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:7768935
  review:
    summary: Direct evidence of ERK2 Ser/Thr kinase activity (TTP phosphorylation).
      Core MF. The deep research notes that ERK1/2 substrates contain a Ser/Thr-Pro
      consensus.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
- term:
    id: GO:0060716
    label: labyrinthine layer blood vessel development
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Placental developmental process inferred by orthology; downstream.
    action: KEEP_AS_NON_CORE
    reason: Developmental process; non-core.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:7889942
  review:
    summary: Direct evidence of nucleoplasmic ERK (Elk-1 phosphorylation context). Core
      nuclear localization.
    action: ACCEPT
    reason: Core nuclear localization with direct evidence.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15781236
  review:
    summary: Caveolin-2/insulin/cell-cycle interaction context; the generic protein
      binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The protein binding term is non-informative per curation guidelines.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:15781236
  review:
    summary: ERK in a protein complex; generic and uninformative as a cellular
      component.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic component term that adds little functional information; the
      specific complexes/scaffolds are not characterized here.
- term:
    id: GO:0031435
    label: mitogen-activated protein kinase kinase kinase binding
  evidence_type: IPI
  original_reference_id: PMID:12049732
  review:
    summary: ERK2 interacts with MEKK1 (a MAP3K) which ubiquitinates ERK1/2. An
      informative interaction within the cascade module.
    action: KEEP_AS_NON_CORE
    reason: Informative protein-interaction term reflecting ERK2 binding within the
      MAPK module; non-core.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IDA
  original_reference_id: PMID:9714150
  review:
    summary: ERK2 (p42MAPK) immunolocalized to axons in rat CNS; neuronal subcellular
      localization.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific neuronal localization with direct evidence; non-core.
- term:
    id: GO:0032839
    label: dendrite cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:9714150
  review:
    summary: ERK2 immunolocalized to dendritic cytoplasm in rat CNS; neuronal
      localization.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific neuronal localization with direct evidence; non-core.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IDA
  original_reference_id: PMID:9714150
  review:
    summary: ERK2 immunolocalized to the perikaryon (neuronal cell body) in rat CNS.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific neuronal localization with direct evidence; non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-997411
  review:
    summary: Cytosolic localization from a Reactome reaction (AGER binds rat ERK1/2).
      Core localization.
    action: ACCEPT
    reason: Core localization (cytosolic pool, TAS).
- term:
    id: GO:0050853
    label: B cell receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector downstream of the B cell receptor; immune-cell
      pathway context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific upstream pathway context; non-core.
- term:
    id: GO:0050852
    label: T cell receptor signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 is an effector downstream of the T cell receptor; immune-cell
      pathway context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific upstream pathway context; non-core.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IC
  original_reference_id: PMID:15027896
  review:
    summary: Ser/Thr kinase activity inferred by curator. Core MF.
    action: ACCEPT
    reason: Core molecular function.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: IDA
  original_reference_id: PMID:15027896
  review:
    summary: Direct evidence of ERK1/2 (MAP kinase) activation in mesangial cells.
      Core MF.
    action: ACCEPT
    reason: Core molecular function with direct evidence.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:15027896
  review:
    summary: ATP binding/use directly demonstrated. Core MF. The deep research
      independently describes an in vitro kinase assay using active TEY-phosphorylated
      ERK2 and an ATP-gamma-S analog.
    action: ACCEPT
    reason: Core molecular function with direct experimental support.
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:15027896
  review:
    summary: Generic protein phosphorylation (catalytic output) with direct evidence.
    action: KEEP_AS_NON_CORE
    reason: Generic BP output of kinase activity; the MF terms capture this more
      precisely. Non-core.
- term:
    id: GO:0045727
    label: positive regulation of translation
  evidence_type: IMP
  original_reference_id: PMID:15027896
  review:
    summary: ERK promotes protein synthesis in mesangial cells; downstream consequence.
    action: KEEP_AS_NON_CORE
    reason: Downstream regulatory consequence; non-core.
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:17310240
  review:
    summary: ERK response within the growth-factor-induced MAPK network. Core BP.
    action: ACCEPT
    reason: Core biological process (generic parent of ERK1/2 cascade) with
      experimental support.
- term:
    id: GO:0031663
    label: lipopolysaccharide-mediated signaling pathway
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK acts downstream of LPS/TLR signaling; stimulus-specific pathway
      context inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific pathway context; non-core.
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Stimulus-specific cellular response inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0043330
    label: response to exogenous dsRNA
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Stimulus-specific cellular response inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0045596
    label: negative regulation of cell differentiation
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK signaling modulates differentiation; a pleiotropic, context-dependent
      downstream process inferred by orthology.
    action: KEEP_AS_NON_CORE
    reason: Context-dependent downstream process; non-core.
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IEP
  original_reference_id: PMID:15583728
  review:
    summary: ERK1/2 drives proliferation (thrombin-induced VSMC proliferation
      context). A major but downstream pleiotropic outcome of cascade activity.
    action: KEEP_AS_NON_CORE
    reason: Major downstream consequence of ERK activity, but context-dependent and
      not the protein's core molecular role. Kept as non-core.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IEP
  original_reference_id: PMID:15917991
  review:
    summary: ERK1/2 promotes cell migration (MCP-1-stimulated VSMC migration). A
      downstream pleiotropic outcome.
    action: KEEP_AS_NON_CORE
    reason: Downstream consequence of ERK activity; non-core.
- term:
    id: GO:0043627
    label: response to estrogen
  evidence_type: IDA
  original_reference_id: PMID:11751611
  review:
    summary: ERK2 activation in estrogen-induced neuroprotection; stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0097237
    label: cellular response to toxic substance
  evidence_type: IDA
  original_reference_id: PMID:12487375
  review:
    summary: ERK activation by acrolein in vascular smooth muscle; stimulus-specific
      response.
    action: KEEP_AS_NON_CORE
    reason: Stimulus-specific response; non-core.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Generic parent of the specific kinase MF terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general MF; the specific MAP kinase / protein serine/threonine kinase
      terms are present and preferred.
- term:
    id: GO:0019858
    label: cytosine metabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK2 has no established role in cytosine metabolism; this orthology
      transfer is almost certainly spurious/erroneous.
    action: REMOVE
    reason: Biologically implausible. ERK2 is a protein kinase with no role in
      pyrimidine/cytosine metabolism. This appears to be an erroneous orthology
      transfer and should be removed.
- term:
    id: GO:0019233
    label: sensory perception of pain
  evidence_type: IMP
  original_reference_id: PMID:11356865
  review:
    summary: ERK signaling required for inflammatory pain (via mGluR1/5); an
      organism-level physiological process downstream of the cascade.
    action: KEEP_AS_NON_CORE
    reason: Physiological process; non-core.
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: ERK signaling participates in DNA damage responses in some contexts;
      downstream/context-specific.
    action: KEEP_AS_NON_CORE
    reason: Context-specific downstream process; non-core.
- term:
    id: GO:0004707
    label: MAP kinase activity
  evidence_type: TAS
  original_reference_id: PMID:9779826
  review:
    summary: MAP kinase activity (TAS, postnatal heart development study). Core MF.
    action: ACCEPT
    reason: Core molecular function.
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: TAS
  original_reference_id: PMID:9779826
  review:
    summary: Generic protein phosphorylation (catalytic output, TAS).
    action: KEEP_AS_NON_CORE
    reason: Generic BP output; non-core relative to MF terms.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: TAS
  original_reference_id: PMID:11687663
  review:
    summary: Generic kinase activity (TAS). Over-general.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general MF; specific kinase terms preferred.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IDA
  original_reference_id: PMID:12072413
  review:
    summary: ERK1/2 in vitamin-D-modulated chondrocyte signaling; generic
      signal-transduction parent.
    action: KEEP_AS_NON_CORE
    reason: Generic BP parent; the ERK1/2 cascade term is preferred. Non-core.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: TAS
  original_reference_id: PMID:9779826
  review:
    summary: Generic intracellular signal transduction (TAS).
    action: KEEP_AS_NON_CORE
    reason: Generic BP parent; non-core.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Generic parent of the specific kinase MF terms (ISO duplicate).
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general MF; specific MAP kinase / Ser/Thr kinase terms preferred.
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: This implies ERK2 binds phosphotyrosine residues. ERK2 does engage
      phosphorylated docking partners, but a dedicated phosphotyrosine-binding MF is
      not an established ERK2 function and likely over-annotates by orthology transfer.
    action: MARK_AS_OVER_ANNOTATED
    reason: Not an established ERK2 molecular function; ERK2 lacks a canonical
      phosphotyrosine-binding module (e.g., SH2/PTB). Likely an erroneous/over-broad
      orthology transfer.
- term:
    id: GO:0009887
    label: animal organ morphogenesis
  evidence_type: ISO
  original_reference_id: GO_REF:0000121
  review:
    summary: Generic developmental morphogenesis process inferred by orthology;
      pleiotropic and downstream.
    action: KEEP_AS_NON_CORE
    reason: Generic developmental process; non-core.
core_functions:
- description: ERK2 is the terminal serine/threonine protein kinase of the canonical
    RAS-RAF-MEK-ERK (ERK1/2) MAPK cascade. Activated by MEK1/2-mediated dual
    phosphorylation of its TEY activation-loop motif, it uses ATP to phosphorylate
    Ser/Thr-Pro motifs on a broad set of cytoplasmic and nuclear substrates,
    transducing signals from growth factor receptors and other stimuli into cellular
    responses such as proliferation and differentiation.
  molecular_function:
    id: GO:0004707
    label: MAP kinase activity
  directly_involved_in:
  - id: GO:0070371
    label: ERK1 and ERK2 cascade
  - id: GO:0000165
    label: MAPK cascade
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:15027896
    supporting_text: Angiotensin II-induced ERK1/ERK2 activation
  - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
    supporting_text: |-
      Mapk1 encodes ERK2**, a serine/threonine MAP kinase in the canonical RAS→RAF→MEK→ERK cascade
  - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
    supporting_text: |-
      ERK1/2 substrates contain a **Ser/Thr‑Pro** consensus
- description: ERK2 binds ATP in its kinase domain and transfers the gamma-phosphate
    to Ser/Thr residues of substrate proteins; ATP binding is required for the
    phosphotransfer reaction that underlies all ERK2 signaling.
  molecular_function:
    id: GO:0005524
    label: ATP binding
  directly_involved_in:
  - id: GO:0070371
    label: ERK1 and ERK2 cascade
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:15027896
    supporting_text: Angiotensin II-induced ERK1/ERK2 activation and protein synthesis
      are redox-dependent in glomerular mesangial cells
  - reference_id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
    supporting_text: |-
      an in vitro kinase assay with active TEY-phosphorylated ERK2 and an ATPγS analog
proposed_new_terms: []
suggested_questions:
- question: To what extent are the many ISO-inferred developmental and tissue-specific
    process annotations (e.g., thyroid/thymus/face/lung development) representative
    of an endogenous rat Mapk1 requirement versus general ERK1/2 pathway pleiotropy
    shared redundantly with Mapk3/ERK1?
- question: Which ERK2 substrates and localized signaling pools are most relevant in
    rat-specific physiology (e.g., the IMCD EGF-ERK network and NHE1/SLC9A1
    phosphorylation), and how does ERK2 nuclear translocation versus cytoplasmic
    sequestration (PEA-15) shape these outputs?
suggested_experiments:
- hypothesis: Endogenous rat ERK2 (Mapk1) activation drives a defined transcriptional
    program through nuclear translocation, separable from cytoplasmic substrate
    phosphorylation.
  description: Use compartment-restricted ERK2 (constitutively nuclear vs.
    cytoplasm-tethered) in a relevant rat cell system and perform RNA-seq plus
    phosphoproteomics to dissect which downstream processes require nuclear ERK2
    versus cytoplasmic ERK2 activity.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: GO_REF:0000121
  title: RGD ISO annotations to rat from other mammalian species
  findings: []
- id: file:rat/Mapk1/Mapk1-deep-research-falcon.md
  title: Falcon (Edison Scientific) deep research report on rat Mapk1 (ERK2), UniProt
    P63086
  findings:
  - statement: |
      Mapk1 (UniProt P63086) is ERK2, the terminal serine/threonine kinase of the
      canonical RAS-RAF-MEK-ERK cascade, distinct from Mapk3/ERK1.
    supporting_text: |-
      Mapk1 encodes ERK2**, a serine/threonine MAP kinase in the canonical RAS→RAF→MEK→ERK cascade
    reference_section_type: OTHER
  - statement: |
      ERK1/2 are the terminal kinases of the canonical RAS-RAF-MEK-ERK cascade
      downstream of many membrane receptors, with outputs including proliferation,
      differentiation, EMT, senescence, and cell death depending on signal strength,
      duration, context, and spatial localization.
    supporting_text: |-
      ERK1/2 (MAPK3/MAPK1) are described as **terminal kinases** in the canonical **RAS→RAF→MEK→ERK** cascade downstream of many membrane receptors, with outputs that include proliferation, differentiation, epithelial–mesenchymal transition (EMT), senescence, and cell death
    reference_section_type: OTHER
  - statement: |
      ERK2 is a serine/threonine kinase; in the rat IMCD phosphoproteomic resource
      ERK-family proteins are annotated under a serine/threonine kinase domain
      category.
    supporting_text: |-
      ERK family proteins are annotated under a **serine/threonine kinase domain category**
    reference_section_type: OTHER
  - statement: |
      ERK2 is activated by dual phosphorylation of the TEY activation-loop motif
      (T179/Y185 in the rat UniProt-mapped table), directly observed for rat
      Mapk1/ERK2.
    supporting_text: |-
      Dual phosphorylation in the TEY activation segment region** is directly observed for rat Mapk1/ERK2
    reference_section_type: OTHER
  - statement: |
      In native rat IMCD cells, MEK2 (Map2k2) activity is placed upstream of Mapk1
      phosphorylation, and EGF activates the canonical MAPK pathway in this rat
      tissue context.
    supporting_text: |-
      the same rat IMCD network links **Map2k2 (MEK2)** activity to Mapk1 phosphorylation
    reference_section_type: OTHER
  - statement: |
      Pathway enrichment in native rat IMCD cells confirms engagement of RAF-MEK-ERK
      signaling after EGF stimulation.
    supporting_text: |-
      pathway enrichment confirms engagement of **RAF–MEK–ERK signaling**
    reference_section_type: OTHER
  - statement: |
      ERK1/2 phosphorylate substrates containing a Ser/Thr-Pro consensus motif.
    supporting_text: |-
      ERK1/2 substrates contain a **Ser/Thr‑Pro** consensus
    reference_section_type: OTHER
  - statement: |
      ERK2 kinase activity uses ATP; an in vitro kinase assay with active
      TEY-phosphorylated ERK2 and an ATPgammaS analog was used to test substrate
      phosphorylation.
    supporting_text: |-
      an in vitro kinase assay with active TEY-phosphorylated ERK2 and an ATPγS analog
    reference_section_type: OTHER
  - statement: |
      ERK2 localization is a key regulatory feature: transcriptional outcomes often
      require nuclear ERK, and PEA-15 binds ERK, contains a nuclear export sequence,
      and can prevent nuclear accumulation of ERK.
    supporting_text: |-
      PEA‑15** binds ERK and (i) contains a nuclear export sequence, and (ii) can **prevent nuclear accumulation** of ERK
    reference_section_type: OTHER
  - statement: |
      ERK2 signaling is organized via membrane/cytoplasmic scaffolds; the NHE1/Slc9a1
      Na+/H+ exchanger can act as a membrane scaffold for ERK2, which phosphorylates
      NHE1.
    supporting_text: |-
      NHE1/Slc9a1** can act as a **membrane scaffold** for ERK2
    reference_section_type: OTHER
  - statement: |
      ERK2 is linked to translation-control nodes (e.g., Eif4ebp1 and Eef2k) in the
      rat IMCD EGF network.
    supporting_text: |-
      ERK2 is also linked to translation-control nodes including Eif4ebp1 and Eef2k
    reference_section_type: OTHER
- id: PMID:11356865
  title: Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular
    signal-regulated kinase signaling required for inflammatory pain in mice.
  findings: []
- id: PMID:11404397
  title: 'Beta-amyloid activates the mitogen-activated protein kinase cascade via
    hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms
    related to Alzheimer''s disease.'
  findings: []
- id: PMID:11679970
  title: 'Defective mitogen-activated protein kinase (ERK2) signaling in gastric mucosa
    of portal hypertensive rats: potential therapeutic implications.'
  findings: []
- id: PMID:11687663
  title: Cyclic changes in estradiol regulate synaptic plasticity through the MAP
    kinase pathway.
  findings: []
- id: PMID:11751611
  title: 'Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone
    and 19-norprogesterone and antagonism by medroxyprogesterone acetate.'
  findings: []
- id: PMID:11875501
  title: 'Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting
    colon cancer growth and gastrointestinal hypertrophy.'
  findings: []
- id: PMID:12049732
  title: The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination
    and degradation of ERK1/2.
  findings: []
- id: PMID:12072413
  title: 1alpha,25-dihydroxyvitamin D(3) and 24R,25-dihydroxyvitamin D(3) modulate
    growth plate chondrocyte physiology via protein kinase C-dependent phosphorylation
    of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase.
  findings: []
- id: PMID:12487375
  title: Acrolein activates mitogen-activated protein kinase signal transduction pathways
    in rat vascular smooth muscle cells.
  findings: []
- id: PMID:12944431
  title: 'DOC1R: a MAP kinase substrate that control microtubule organization of metaphase
    II mouse oocytes.'
  findings: []
- id: PMID:15027896
  title: Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent
    in glomerular mesangial cells.
  findings: []
- id: PMID:15583728
  title: The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle
    cell proliferation and attenuates intimal thickening after balloon injury.
  findings: []
- id: PMID:15781236
  title: Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B
    fibroblast cells.
  findings: []
- id: PMID:15893655
  title: 17-Beta estradiol rapidly enhances extracellular signal-regulated kinase
    2 phosphorylation in the rat brain.
  findings: []
- id: PMID:15917991
  title: Reactive oxygen species and ERK 1/2 mediate monocyte chemotactic protein-1-stimulated
    smooth muscle cell migration.
  findings: []
- id: PMID:16943189
  title: cGMP-dependent protein kinase type I inhibits TAB1-p38 mitogen-activated
    protein kinase apoptosis signaling in cardiac myocytes.
  findings: []
- id: PMID:16955078
  title: Alterations in mammalian target of rapamycin signaling pathways after traumatic
    brain injury.
  findings: []
- id: PMID:17310240
  title: Growth factor-induced MAPK network topology shapes Erk response determining
    PC-12 cell fate.
  findings: []
- id: PMID:17651772
  title: MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at
    a dose causing a significant incidence of renal carcinoma.
  findings: []
- id: PMID:19200235
  title: Dopamine promotes striatal neuronal apoptotic death via ERK signaling cascades.
  findings: []
- id: PMID:19457111
  title: Signaling pathway adaptations and novel protein kinase A substrates related
    to behavioral sensitization to cocaine.
  findings: []
- id: PMID:19524539
  title: LysRS serves as a key signaling molecule in the immune response by regulating
    gene expression.
  findings: []
- id: PMID:19565474
  title: The ERK signaling cascade--views from different subcellular compartments.
  findings: []
- id: PMID:21070949
  title: Phosphorylation of DCC by ERK2 is facilitated by direct docking of the receptor
    P1 domain to the kinase.
  findings: []
- id: PMID:21248290
  title: Ovarian steroid receptors and activated MAPK in the regional decidualization
    in rats.
  findings: []
- id: PMID:21790671
  title: Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following
    alcohol binge in chronically ethanol-fed rats.
  findings: []
- id: PMID:22265242
  title: Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate
    gyrus mediates the antidepressant effects of testosterone.
  findings: []
- id: PMID:22521590
  title: Sex differences in social interaction behaviors in rats are mediated by extracellular
    signal-regulated kinase 2 expression in the medial prefrontal cortex.
  findings: []
- id: PMID:22676582
  title: Activation of Nrf2 is required for up-regulation of the π class of glutathione
    S-transferase in rat primary hepatocytes with L-methionine starvation.
  findings: []
- id: PMID:24567387
  title: MURC/Cavin-4 facilitates recruitment of ERK to caveolae and concentric cardiac
    hypertrophy induced by α1-adrenergic receptors.
  findings: []
- id: PMID:26884868
  title: MAPK1 up-regulates the expression of MALAT1 to promote the proliferation
    of cardiomyocytes through PI3K/AKT signaling pathway.
  findings: []
- id: PMID:26950759
  title: Phosphorylation or Mutation of the ERK2 Activation Loop Alters Oligonucleotide
    Binding.
  findings: []
- id: PMID:29959233
  title: Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal
    degradation of connexin-43.
  findings: []
- id: PMID:7478291
  title: ERK2-type mitogen-activated protein kinase (MAPK) and its substrates in postsynaptic
    density fractions from the rat brain.
  findings: []
- id: PMID:7768935
  title: Phosphorylation of tristetraprolin, a potential zinc finger transcription
    factor, by mitogen stimulation in intact cells and by mitogen-activated protein
    kinase in vitro.
  findings: []
- id: PMID:7889942
  title: ERK phosphorylation potentiates Elk-1-mediated ternary complex formation
    and transactivation.
  findings: []
- id: PMID:8223435
  title: cAMP antagonizes p21ras-directed activation of extracellular signal-regulated
    kinase 2 and phosphorylation of mSos nucleotide exchange factor.
  findings: []
- id: PMID:8246947
  title: Epidermal growth factor induces phosphorylation of extracellular signal-regulated
    kinase 2 via multiple pathways.
  findings: []
- id: PMID:9235900
  title: Insulin-like growth factor-I rapidly activates multiple signal transduction
    pathways in cultured rat cardiac myocytes.
  findings: []
- id: PMID:9714150
  title: Immunolocalization of the mitogen-activated protein kinases p42MAPK and JNK1,
    and their regulatory kinases MEK1 and MEK4, in adult rat central nervous system.
  findings: []
- id: PMID:9779826
  title: Expression of mitogen-activated protein kinase pathways during postnatal
    development of rat heart.
  findings: []
- id: Reactome:R-NUL-3245934
  title: Mapk1 (Erk2) phosphorylates ERF
  findings: []
- id: Reactome:R-NUL-997411
  title: AGER binds rat ERK1/2
  findings: []