id: A0A9L0RWM8
gene_symbol: PEA15
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9796
  label: Equus caballus
description: PEA15 (PEA-15/PED) is a small, non-catalytic cytoplasmic phosphoprotein made of an N-terminal
  death-effector domain (DED) and a flexible C-terminal tail. It binds the MAP kinases ERK1 and ERK2
  through a bipartite interface (the DED engages the ERK DEF docking site and the C-terminal tail the
  D-recruitment site), holding them in the cytoplasm and keeping them from nuclear substrates, while
  protecting bound ERK from dephosphorylation so that it is rapidly active when released. Phosphorylation
  of the tail (Ser104 by PKC, Ser116 by CaMKII/Akt) shifts PEA15 between ERK-bound and FADD-bound states.
  Through DED interactions with FADD and caspase-8 it inhibits Fas- and TNFR1-triggered caspase-8 activation
  and extrinsic apoptosis. In mammalian cells it also affects glucose uptake indirectly, by altering
  glucose-transporter trafficking. The horse gene model A0A9L0RWM8 contains the entire 130-residue conserved
  mammalian PEA15 sequence (identical to human) preceded by a predicted 46-residue N-terminal extension
  of unknown significance.
existing_annotations:
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  supporting_entities:
  - InterPro:IPR029546
  review:
    summary: InterPro2GO mapping from the PEA15-specific DED signature. PEA15 is not a kinase or a cascade
      scaffold; it binds ERK1/2 and controls their localization and activation state, i.e. it regulates
      the ERK1/2 cascade.
    action: MODIFY
    reason: The mammalian experimental work places PEA15 as a regulator of ERK1/2 signalling rather than
      a component that transmits the phosphorylation relay. It binds ERK, blocks ERK nuclear entry and
      ERK-dependent transcription (PMID:11702783), and in the ERK2 complex holds the activation loop in
      an inactive conformation while protecting it from dephosphorylation (PMID:23575685). Its net effect
      can be inhibitory (cytoplasmic retention) or permissive (accumulation of releasable phospho-ERK),
      so the unsigned regulation term GO:0070372 regulation of ERK1 and ERK2 cascade, a regulation term
      for the MAPK cascade subtype it acts on, is the accurate replacement. Transfer to horse is supported
      by membership of PANTHER PTHR48169:SF1 (with human, mouse and rat PEA15) and by 130/130 identity of
      the horse model's conserved core to human PEA15, including the C-terminal ERK-docking segment and
      DED (file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md).
    proposed_replacement_terms:
    - id: GO:0070372
      label: regulation of ERK1 and ERK2 cascade
    supported_by:
    - reference_id: PMID:11702783
      supporting_text: PEA-15 can redirect the biological outcome of MAP kinase signaling by regulating
        the subcellular localization of ERK MAP kinase.
    - reference_id: PMID:23575685
      supporting_text: even though ERK bound to PEA-15 is phosphorylated, its activation loop is held
        in an inactive conformation (Fig. 4b) and its nuclear transport is blocked
    - reference_id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md
      supporting_text: '| C-terminal ERK D-site segment 121-129 | 167-175 | 9/9 |'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  supporting_entities:
  - UniProtKB-SubCell:SL-0086
  review:
    summary: PEA15 is a soluble cytoplasmic protein; its best-characterized activity is anchoring ERK in
      the cytoplasm.
    action: ACCEPT
    reason: Curated human UniProt localization is cytoplasm, and the mouse/human functional data show that
      PEA15 anchors ERK in the cytoplasm via its nuclear export sequence (PMID:11702783). The NES (human
      residues 7-17) is fully conserved in the horse model (positions 53-63). The predicted N-terminal extension
      has no recognizable signal peptide or transmembrane segment, so nothing argues for a different compartment,
      although its effect on localization is untested. Cytoplasm is the appropriate level; cytosol would
      also be defensible but cytoplasm is accepted as is.
    supported_by:
    - reference_id: file:human/PEA15/PEA15-uniprot.txt
      record_section: ["CC:SUBCELLULAR LOCATION"]
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
    - reference_id: PMID:11702783
      supporting_text: PEA-15 contains a nuclear export sequence required for its capacity to anchor ERK
        in the cytoplasm.
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  supporting_entities:
  - InterPro:IPR001875
  - InterPro:IPR029546
  review:
    summary: Correct but general; PEA15's apoptotic role is specifically inhibition of death-receptor (Fas/TNFR1)
      signalling at the FADD/caspase-8 step.
    action: MODIFY
    reason: The experimental mechanism is DED-dependent interference with FADD-caspase-8 (FLICE) association
      downstream of Fas and TNFR1 (PMID:10442631). The specific descendant GO:1902042 negative regulation
      of extrinsic apoptotic signaling pathway via death domain receptors is already carried by this horse
      protein (ARBA row below) and is the term PAINT propagates at the PEA15 node, so the general term
      is refined to it rather than kept alongside it.
    proposed_replacement_terms:
    - id: GO:1902042
      label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
    supported_by:
    - reference_id: PMID:10442631
      supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated

        apoptosis.'
- term:
    id: GO:1902042
    label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  supporting_entities:
  - ARBA:ARBA00088654
  review:
    summary: PEA15 inhibits Fas/TNFR1-induced caspase-8 activation and apoptosis via its DED.
    action: ACCEPT
    reason: Human primary data show PEA15 co-precipitates with FADD and FLICE (caspase-8), reduces FADD-FLICE
      association and caspase-8 activation, and protects from FAS- and TNFR1-mediated apoptosis (PMID:10442631).
      Evolutionary grounding for horse does not rest on the ARBA rule alone - PAINT curators placed this
      term (as IBA, on the human and mouse orthologs) at the PEA15 ancestral node of PTHR48169, and the
      horse model sits in the same subfamily (PTHR48169:SF1) with a DED identical to human. The predicted
      horse N-terminal extension lies outside the DED and has not been tested.
    supported_by:
    - reference_id: PMID:10442631
      supporting_text: PED/PEA-15 co-precipitated with both FADD and FLICE.
    - reference_id: PMID:10442631
      supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated

        apoptosis.'
    - reference_id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md
      supporting_text: '| DED (UniProt FT 3-81) | 49-127 | 79/79 |'
- term:
    id: GO:0140311
    label: protein sequestering activity
  evidence_type: ISS
  original_reference_id: PMID:11702783
  qualifier: enables
  review:
    summary: PEA15 binds ERK1/2 and anchors them in the cytoplasm, preventing their nuclear localization;
      this is its best-established molecular activity and is not captured by any existing horse annotation.
    action: NEW
    reason: GO:0140311 is defined as binding a protein to inhibit its localization to where it is active,
      which matches NES-dependent cytoplasmic anchoring of ERK by PEA15 (PMID:11702783) and the structural
      basis of ERK2 capture (PMID:23575685). Transfer is by orthology within PANTHER PTHR48169:SF1, with
      the horse conserved core identical to human, including the NES and both ERK-docking surfaces (file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md).
      This is a molecular function of the gene product itself, not a downstream phenotype.
    supported_by:
    - reference_id: PMID:11702783
      supporting_text: PEA-15 contains a nuclear export sequence required for its capacity to anchor ERK
        in the cytoplasm.
    - reference_id: PMID:23575685
      supporting_text: even though ERK bound to PEA-15 is phosphorylated, its activation loop is held
        in an inactive conformation (Fig. 4b) and its nuclear transport is blocked
    - reference_id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md
      supporting_text: '| NES (residues 7-17) | 53-63 | 11/11 |'
- term:
    id: GO:0035877
    label: death effector domain binding
  evidence_type: ISS
  original_reference_id: PMID:10442631
  qualifier: enables
  review:
    summary: The PEA15 DED associates with the DED-containing proteins FADD and caspase-8 (FLICE), the interaction
      through which it blocks death-receptor signalling.
    action: NEW
    reason: Human PEA15 co-precipitates with FADD and FLICE, overexpressed FADD competes with the PEA15-FLICE association only
      when it retains its DED, and the inhibitory effect is attributed to the PEA15 DED (PMID:10442631). The human GOA records
      these interactions only as uninformative protein binding; death effector domain binding states the
      informative activity. The horse DED is identical to human (79/79) within PTHR48169:SF1. Proposed
      as an MF only; no new process term is added.
    supported_by:
    - reference_id: PMID:10442631
      supporting_text: PED/PEA-15-FLICE association was inhibited by overexpression of the wild-type but
        not of a DED-deletion mutant of FADD.
    - reference_id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md
      supporting_text: '| DED (UniProt FT 3-81) | 49-127 | 79/79 |'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: file:human/PEA15/PEA15-uniprot.txt
  title: 'UniProtKB Q15121: human PEA15 curated sequence and functions'
  findings: []
- id: file:HORSE/PEA15/PEA15-uniprot.txt
  title: 'UniProtKB A0A9L0RWM8: horse PEA15 sequence'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Unreviewed TrEMBL gene model (Ensembl ENSECAT00000100520, gene ENSECAG00000019187, 176
      aa). Used for sequence and domain/family placement only; its ARBA-derived names, keywords and localization
      are not used as evidence.
- id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS.md
  title: PEA15 human–horse sequence comparison
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reproducible Biopython global alignment with retained full output, sequence
      hashes and scoring parameters; computed, not hardcoded. The complete 130-residue human
      PEA15 sequence pairs identically to part of the selected horse model, but the 176-residue
      horse model also contains unpaired sequence, and the sidecar maps no individual ERK-,
      death-effector-domain-, or phosphorylation-site features. Superseded for feature mapping
      by RESULTS-rereview.md in the 2026-10-20 re-review; kept as the original analysis.
- id: file:HORSE/PEA15/PEA15-bioinformatics/RESULTS-rereview.md
  title: 'PEA15 re-review: horse gene models vs human/mouse PEA15'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: New script compare_sequences_rereview.py (2026-10-20) aligning both horse TrEMBL models
      (A0A9L0RWM8, F7AD02) and mouse Q62048 to human Q15121 with free end gaps, mapping the DED, NES,
      D74, S104, S116 and the C-terminal ERK-docking segment. Shows human Met1 at horse position 47 and
      a 46-aa predicted N-terminal extension.
- id: PMID:23575685
  title: Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached. Crystal structures of human PEA-15 with ERK2; bipartite docking, allosteric
      inactivation and protection from dephosphorylation.
- id: PMID:10442631
  title: 'PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; human cell lines; source of the human IDA for GO:1902042.
- id: PMID:9670003
  title: PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Abstract-only. Overexpression of human PED in L6 cells altered GLUT1/GLUT4 surface levels.
      Not used as support for any horse annotation; PAINT did not propagate the glucose-import regulation
      term, and no NEW annotation is proposed from it. Kept as background.
- id: PMID:11702783
  title: PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached. Establishes ERK binding, NES-dependent cytoplasmic anchoring of ERK and
      increased ERK nuclear localization on genetic deletion.
core_functions:
- description: Binds ERK1/2 through its DED and C-terminal docking segment and retains them in the cytoplasm,
    away from nuclear substrates, while protecting bound phospho-ERK from dephosphorylation; this regulates
    the output of the ERK1/2 cascade.
  molecular_function:
    id: GO:0140311
    label: protein sequestering activity
  directly_involved_in:
  - id: GO:0070372
    label: regulation of ERK1 and ERK2 cascade
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:11702783
    supporting_text: blocks ERK-dependent transcription and proliferation by binding ERKs and preventing
      their localization in the nucleus
  - reference_id: PMID:23575685
    supporting_text: occupying two key docking sites of ERK2
- description: Uses its death-effector domain to engage FADD and caspase-8 at death receptors, reducing
    FADD-caspase-8 association and caspase-8 activation and thereby inhibiting Fas/TNFR1-induced extrinsic
    apoptosis.
  molecular_function:
    id: GO:0035877
    label: death effector domain binding
  directly_involved_in:
  - id: GO:1902042
    label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:10442631
    supporting_text: PED/PEA-15 co-precipitated with both FADD and FLICE.
suggested_questions:
- question: Is the predicted 46-residue N-terminal extension of horse A0A9L0RWM8 (and the 9-residue extension
    of F7AD02) translated in horse tissues, or are these gene-model artifacts from upstream in-frame ATGs/alternative
    5' exons, with the native product starting at the conserved MAEY Met (position 47)?
- question: If the extension is translated, does it alter PEA15 NES-dependent ERK sequestration or the
    N-terminal PLD1-binding surface (human residues 1-24)?
suggested_experiments:
- description: N-terminal proteomics or western blotting of horse astrocyte/brain lysate with a PEA15
    antibody to determine whether the native protein is ~15 kDa (130 aa) or ~20 kDa (176 aa).
  experiment_type: proteomics