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.
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.
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).
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
Summary: PEA15 is a soluble cytoplasmic protein; its best-characterized activity is anchoring ERK in the cytoplasm.
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.
Summary: Correct but general; PEA15's apoptotic role is specifically inhibition of death-receptor (Fas/TNFR1) signalling at the FADD/caspase-8 step.
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.
Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis.
GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
IEA GO_REF:0000117
ACCEPT
Summary: PEA15 inhibits Fas/TNFR1-induced caspase-8 activation and apoptosis via its DED.
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.
ISS PMID:11702783 PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase.
NEW
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.
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.
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
ISS PMID:10442631 PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TN...
NEW
Summary: The PEA15 DED associates with the DED-containing proteins FADD and caspase-8 (FLICE), the interaction through which it blocks death-receptor signalling.
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.
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.
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.
Q: 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)?
Q: 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
Experiment: 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).
Type: proteomics
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
PEA15 is a non-catalytic DED-containing cytoplasmic protein that anchors ERK1/2 and inhibits death-receptor-induced apoptosis. In mammalian cells it regulates glucose-transporter trafficking indirectly, through phospholipase D1 and PKC-alpha signalling, so the single ProtNLM2 carbohydrate-transport prediction for the horse protein remains uncertain.
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: The horse gene model carries the complete human PEA15 core at 100% identity (with a 46-residue N-terminal extension) in PANTHER subfamily PTHR48169:SF1, so human PEA15 evidence transfers to it. That evidence shows PEA15 regulates glucose transport rather than performing it. Overexpressed human PEA15 in L6 myotubes raises surface GLUT1 and inhibits insulin-stimulated glucose transport and GLUT4 recruitment, and this effect is mediated indirectly through PEA15 binding to the phospholipase D1 D4 domain and the consequent increase in PKC-alpha activity. The human gene review keeps only the regulatory term GO:0046325 (negative regulation of D-glucose import across plasma membrane), as non-core, and notes that PEA15 has no transporter activity; the horse GOA set has no carbohydrate-transport or glucose-import term. GO:0008643 asserts participation in directed carbohydrate movement, and a regulation term is not an is_a descendant of the regulated process, so the existing regulatory evidence neither supports nor overlaps the prediction. PEA15 is not shown to take part in the transport step itself, but no evidence directly excludes a participatory role, so the prediction remains uncertain rather than refuted.
Supporting Evidence:
PMID:9670003: "Transfection of PED/PEA-15 in differentiating L6 skeletal muscle cells increases the content of Glut1 transporters on the plasma membrane and inhibits insulin-stimulated glucose transport and cell-surface recruitment of Glut4"
PMID:18541525: "PED/PEA-15 overexpression impairs insulin regulation of glucose transport, and this is mediated by its interaction with the C-terminal D4 domain of phospholipase D1 (PLD1) and the consequent increase of protein kinase C-alpha activity"