PEA15 (PEA-15/PED) is a small (130 aa), ubiquitously expressed cytoplasmic phosphoprotein consisting of an N-terminal death effector domain (DED) and an unstructured C-terminal tail. It binds ERK1/2 (MAPK3/MAPK1) through a bipartite interaction in which the DED occupies the ERK DEF-docking site and the C-terminal tail occupies the D-recruitment site; bound ERK is held in the cytoplasm, its activation loop is distorted into an inactive conformation, and its dually phosphorylated state is protected from phosphatases, so that PEA15 acts as a cytoplasmic anchor and phosphorylation-gated reservoir for active ERK. Phosphorylation of PEA15 at Ser104 (PKC) and Ser116 (CaMKII/AKT) releases ERK. Through its DED, PEA15 also associates with FADD and caspase-8 and inhibits Fas- and TNFR1-induced caspase-8 activation and apoptosis. Overexpression in muscle and adipose cells impairs insulin-stimulated GLUT4 recruitment and glucose uptake.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000165 MAPK cascade | IEA GO_REF:0000002 | MODIFY | Summary: PEA15 regulates ERK1/2 signalling rather than acting as a cascade component. Reason: PEA15 is not a kinase or relay component of the MAPK cascade; it binds ERK1/2 and modulates their localization, conformation and dephosphorylation, inhibiting nuclear ERK signalling while preserving a pool of phospho-ERK that is released on PEA15 phosphorylation. The effect can be positive or negative depending on context, so the accurate process is regulation of the ERK1 and ERK2 cascade. Proposed replacements: regulation of ERK1 and ERK2 cascade Supporting Evidence: PMID:23575685 PEA-15 binding protects ERK2 from dephosphorylation, thus setting the stage for immediate ERK activity upon its release from the PEA-15 inhibitory complex. |
| GO:0005515 protein binding | IPI PMID:10442631 PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TN... | MODIFY | Summary: PEA15 co-precipitates with FADD; the interaction is DED-mediated. Reason: Bare protein binding is uninformative. In MCF-7 and HeLa lysates PEA15 co-precipitated with FADD, and the authors attribute displacement of FADD-caspase-8 binding to the PEA15 death effector domain; FADD binds partners through its own DED. Death effector domain binding captures the informative content of this interaction. Proposed replacements: death effector domain binding Supporting Evidence: PMID:10442631 At least in part, this function may involve displacement of FADD-FLICE binding through the death effector domain of PED/PEA-15. |
| GO:0005515 protein binding | IPI PMID:10442631 PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TN... | MODIFY | Summary: PEA15 co-precipitates with caspase-8 (FLICE). Reason: Bare protein binding is uninformative. PEA15 co-precipitated with caspase-8 (FLICE) and reduced FADD-caspase-8 association and caspase-8 activation in response to TNF-alpha. Caspase binding is the informative replacement; a direct caspase inhibitor activity is not established because the effect is attributed to displacement from FADD rather than to inhibition of the protease. Proposed replacements: caspase binding Supporting Evidence: PMID:10442631 PED/PEA-15 co-precipitated with both FADD and FLICE. |
| GO:0005515 protein binding | IPI PMID:17255949 Mxi2 promotes stimulus-independent ERK nuclear translocation... | MODIFY | Summary: PEA15 binds MAPK1 (ERK2). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:17255949 Mxi2 acts antagonistically to PEA15, displacing it from ERK1/2 complexes |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: TERF2IP interaction from a genome-wide BiFC screen for telomere signalling regulators. Reason: Bare protein binding is uninformative. The TERF2IP (RAP1) interaction derives from a genome-wide YFP fluorescence-complementation screen and has no follow-up establishing a PEA15 function at telomeres or in NF-kappaB signalling; no more informative MF term is supported. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | MODIFY | Summary: PEA15 binds MAPK3 (ERK1). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005515 protein binding | IPI PMID:23575685 Structure of ERK2 bound to PEA-15 reveals a mechanism for ra... | MODIFY | Summary: Crystal structures of PEA15 bound to three ERK2 phospho-conformers. Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. This structural study is the strongest evidence for the interaction, and also supports protein kinase regulator activity (core function). Proposed replacements: mitogen-activated protein kinase binding Supporting Evidence: PMID:23575685 PEA-15 uses a bipartite binding mode, occupying two key docking sites of ERK2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: PEA15 binds MAPK3 (ERK1). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: PEA15 binds MAPK1 (ERK2). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: PEA15 binds MAPK3 (ERK1). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: PEA15 binds MAPK1 (ERK2). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: PEA15 binds MAPK1 (ERK2). Reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. Proposed replacements: mitogen-activated protein kinase binding |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: PEA15 is a cytoplasmic protein. Reason: UniProt and the ERK-anchoring mechanism place PEA15 in the cytoplasm, where it retains ERK1/2 and prevents their nuclear translocation. Supporting Evidence: file:human/PEA15/PEA15-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: PEA15 is a soluble cytosolic ERK anchor. Reason: Immunofluorescence (HPA) and the Reactome curation both place PEA15 in the cytosol, consistent with a soluble DED protein lacking membrane-targeting features that sequesters ERK1/2 outside the nucleus. Supporting Evidence: Reactome:R-HSA-5675206 PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5675206 | ACCEPT | Summary: PEA15 is a soluble cytosolic ERK anchor. Reason: Immunofluorescence (HPA) and the Reactome curation both place PEA15 in the cytosol, consistent with a soluble DED protein lacking membrane-targeting features that sequesters ERK1/2 outside the nucleus. Supporting Evidence: Reactome:R-HSA-5675206 PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus |
| GO:0005875 microtubule associated complex | NAS PMID:8662970 The major astrocytic phosphoprotein PEA-15 is encoded by two... | MODIFY | Summary: Association of PEA15 with microtubules was reported in mouse astrocytes; there is no evidence for a defined complex. Reason: The cited abstract describes PEA-15 as a protein kinase C substrate associated with microtubules, citing earlier mouse astrocyte work; UniProt records the same association. GO:0005875 denotes a multimeric complex connected to microtubules, and no such complex containing PEA15 has been defined. Location on the microtubule cytoskeleton is the claim actually made. This is a non-core, NAS-level observation from the mouse ortholog (same PANTHER subfamily PTHR48169:SF1, 96% identical). Proposed replacements: microtubule cytoskeleton Supporting Evidence: PMID:8662970 PEA-15, a protein kinase C substrate associated with microtubules |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: Correct but general; PEA15 inhibits death-receptor-induced apoptosis specifically. Reason: The InterPro DED mapping is correct in direction but general. The experimental evidence is specifically for inhibition of Fas- and TNFR1-induced apoptosis by interference with FADD-caspase-8 association, which the gene already carries as GO:1902042 (IDA and IBA). Proposed replacements: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Supporting Evidence: PMID:10442631 Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis. |
| GO:0046325 negative regulation of D-glucose import across plasma membrane | IDA PMID:9670003 PED/PEA-15 gene controls glucose transport and is overexpres... | KEEP AS NON CORE | Summary: PEA15 overexpression inhibits insulin-stimulated glucose transport in L6 myotubes. Reason: Overexpression of human PEA15 in L6 skeletal muscle cells inhibited insulin-stimulated glucose transport and GLUT4 recruitment to the surface; the term matches this regulatory observation. It is a gain-of-function phenotype linked to the type 2 diabetes overexpression finding, mediated indirectly (via PLD1/PKC signalling), and peripheral to the core ERK-anchoring and DED functions. PEA15 has no transporter activity. 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 |
| GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors | IBA GO_REF:0000033 | ACCEPT | Summary: PEA15 inhibits Fas- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. Reason: The PAINT node PTN008298780 sits within the PEA15 orthologue clade (PANTHER PTHR48169:SF1) and is grounded in human (this gene, IDA) and mouse Pea15 experimental data; the human protein is a direct descendant, so the inference is sound. The DED-mediated anti-apoptotic function is a defining activity of the PEA15 branch, distinct from the CFLAR (SF3) and caspase-8/10 (SF7) subfamilies. Supporting Evidence: PMID:10442631 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 | IDA PMID:10442631 PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TN... | ACCEPT | Summary: PEA15 inhibits Fas- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. Reason: Primary human-cell experiment: overexpressed PEA15 blocked FasL and TNF-alpha apoptosis, co-precipitated with FADD and caspase-8, reduced FADD-caspase-8 co-precipitation and caspase-8 activation. PEA15 itself performs the inhibitory step, so this is genuine regulatory participation. Supporting Evidence: PMID:10442631 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- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. Reason: Consistent with the experimental IDA and IBA rows for the same term; the ARBA prediction adds nothing independent but asserts a correct claim. Supporting Evidence: PMID:10442631 Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis. |
| GO:0042308 negative regulation of protein import into nucleus | IDA PMID:23575685 Structure of ERK2 bound to PEA-15 reveals a mechanism for ra... | NEW | Summary: PEA15 retains ERK1/2 in the cytoplasm and blocks their nuclear translocation. Reason: PEA15 is the entity that performs this step: by occupying the ERK DEF and D docking sites it masks the surfaces ERK uses to engage nuclear transport machinery. In the structure paper, the PEA15 L123K docking mutant fails to prevent ERK nuclear translocation, and the R71 interface mutant abrogates cytoplasmic retention; Reactome and the Mxi2 study describe the same cytoplasmic-anchor function. This is the direct mechanism rather than a downstream phenotype. Supporting Evidence: PMID:23575685 results in the failure of the PEA-15 L123K mutant to prevent ERK nuclear translocation Reactome:R-HSA-5675206 PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus |
| GO:0019887 protein kinase regulator activity | IDA PMID:23575685 Structure of ERK2 bound to PEA-15 reveals a mechanism for ra... | NEW | Summary: PEA15 directly modulates ERK2 conformation and phosphorylation state. Reason: Crystal structures show that PEA15 binding triggers an allosteric conduit that disrupts key features of active ERK2, holding the activation loop in an inactive conformation, while also protecting the bound kinase from dephosphorylation; interface mutants lose these effects in cells. PEA15 acts directly on the kinase, so a kinase regulator activity is appropriate. A strict inhibitor term is avoided because the net cellular outcome depends on PEA15 phosphorylation and can favour cytoplasmic ERK output. Supporting Evidence: PMID:23575685 PEA-15 binding triggers an extended allosteric conduit in dually phosphorylated ERK2, disrupting key features of active ERK2. |
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Download this section (compressed HTML)Q: Should PEA15 receive a protein sequestering activity (GO:0140311) annotation for ERK1/2 and RSK2, or is protein kinase regulator activity the preferred MF for a cytoplasmic kinase anchor that also protects its target from dephosphorylation?
Q: Does the DED of PEA15 bind FADD directly in purified form, or is co-precipitation with FADD and caspase-8 bridged by other DISC components?
Experiment: Reconstitute FADD-caspase-8 DED filament assembly in vitro with purified PEA15 (wild type, DED mutants, S104/S116 phosphomimetics) to test whether PEA15 caps or displaces filaments directly.
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