{"gene":"PEA15","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1993,"finding":"PEA-15 is a major substrate for protein kinase C (PKC) in astrocytes. In vitro phosphorylation by purified PKC occurs at a consensus site (LTRIPSAKK), and two-dimensional peptide mapping confirmed the same site is phosphorylated in intact cells. PKC mediates the transition from the less acidic (Pa) to the more acidic (Pb) isoelectric form of PEA-15.","method":"In vitro kinase assay with purified PKC, 2D gel electrophoresis, 2D phosphopeptide mapping, partial microsequencing, [32P] labeling of intact astrocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified PKC plus in-cell phosphopeptide mapping confirming identical site; replicated across multiple orthogonal methods in a single rigorous study","pmids":["8449955"],"is_preprint":false},{"year":1998,"finding":"Endothelin-1 stimulation of astrocytes induces phosphorylation of PEA-15 at two distinct sites: Ser104 (the previously identified PKC site) and a novel site Ser116, phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) but not by casein kinase II. CaMKII phosphorylation of Ser116 in vitro facilitates subsequent PKC phosphorylation at Ser104.","method":"Microsequencing of phosphopeptides from endothelin-treated astrocytes, in vitro kinase assay with partly purified CaMKII, 2D phosphopeptide mapping, okadaic acid treatment","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphosite identification by microsequencing combined with in vitro CaMKII kinase assay and in-cell 2D phosphopeptide mapping; multiple orthogonal methods in one study","pmids":["9721757"],"is_preprint":false},{"year":1998,"finding":"PEA-15 overexpression in L6 skeletal muscle cells increases plasma membrane GLUT1 content and inhibits insulin-stimulated glucose transport and cell-surface GLUT4 recruitment. These effects are reversed by PKC inhibition, placing PEA-15 upstream of PKC in glucose transport regulation.","method":"Stable transfection of L6 cells, glucose transport assay, surface GLUT4 measurement, PKC inhibitor rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean overexpression with defined functional readout (glucose uptake, GLUT4 surface levels) plus pharmacological epistasis; independently replicated in subsequent transgenic mouse work","pmids":["9670003"],"is_preprint":false},{"year":1998,"finding":"The death effector domain (DED) of PEA-15 is required for its ability to block Ras-mediated suppression of integrin activation. PEA-15 acts through a pathway involving the small GTPase R-Ras (blocked by dominant-negative R-Ras) rather than by blocking ERK MAP kinase activation downstream of Ras.","method":"Expression cloning, dominant-negative R-Ras rescue, integrin activation assay, DED deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with dominant-negative R-Ras plus DED mutant, single lab","pmids":["9852038"],"is_preprint":false},{"year":1999,"finding":"PEA-15 binds to FADD and FLICE (caspase-8) through its death effector domain, displacing FADD-FLICE interaction and thereby blocking TNFα- and FasL-induced apoptosis. Overexpression of a FADD DED-deletion mutant blocked PEA-15–FLICE association, and TNFα reduced PEA-15 association with endogenous FADD and FLICE.","method":"Co-immunoprecipitation from MCF-7 and HeLa cell lysates, PARP cleavage assay for FLICE (caspase-8) activity, DED-deletion mutant FADD overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with multiple interactors plus functional FLICE activation readout and mutant rescue; replicated in independent labs (PMID 10493725)","pmids":["10442631"],"is_preprint":false},{"year":1999,"finding":"PEA-15 knockout in mice demonstrates that endogenous PEA-15 expression protects astrocytes from TNFα-induced apoptosis in vitro. PEA-15 null astrocytes show increased death after TNFα exposure, and in vitro assays confirm PEA-15 binding to FADD and caspase-8 as the mechanistic basis.","method":"PEA-15 null mutant mouse generation, in vitro astrocyte apoptosis assay, in vitro binding assays for FADD and caspase-8","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype (astrocyte survival) plus direct binding assay; independent confirmation of PMID 10442631","pmids":["10493725"],"is_preprint":false},{"year":2000,"finding":"PEA-15 activates the ERK MAP kinase pathway in a Ras-dependent manner: PEA-15 expression in CHO cells increases Ras GTP loading, MEK and ERK activity, and bypasses the anchorage-dependence of ERK activation. The DED of PEA-15 is required for this ERK-activating function.","method":"ERK/MEK kinase assays, Ras-GTP pull-down, anchorage-independent ERK activation assay, DED deletion mutant analysis in CHO cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (Ras-GTP loading, kinase activity) with DED mutant; single lab","pmids":["10982386"],"is_preprint":false},{"year":2000,"finding":"PEA-15 interacts with phospholipase D1 (PLD1) and PLD2. The PLD1-interacting site on PEA-15 encompasses part of the DED plus C-terminal flanking sequences, overlapping the RhoA-interacting site on PLD1. PEA-15 co-expression increases PLD1 protein expression levels (faster accumulation, longer persistence) without directly affecting PLD1 enzymatic activity, suggesting PEA-15 acts as a PLD chaperone/stabilizer.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro PLD activity assay, co-expression stability analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus in vitro activity assay; single lab","pmids":["10926929"],"is_preprint":false},{"year":2001,"finding":"PEA-15 mediates cytoplasmic sequestration of ERK1/2 MAP kinases by binding ERKs and preventing their nuclear localization. PEA-15 contains a nuclear export sequence required for cytoplasmic ERK anchoring. Genetic deletion of PEA-15 results in increased ERK nuclear localization, increased cFos transcription, and increased cell proliferation.","method":"PEA-15 knockout mouse cells, nuclear export sequence mutant, ERK localization imaging, cFos reporter assay, cell proliferation assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined localization and transcriptional phenotype, plus nuclear export sequence mutant; replicated in multiple subsequent studies","pmids":["11702783"],"is_preprint":false},{"year":2001,"finding":"In L6 skeletal muscle cells overexpressing PED/PEA-15, PKC-α and PKC-β are constitutively activated and inhibit PKC-ζ insulin responsiveness. Blockade of PKC-α (more effectively than PKC-β) restores insulin activation of PKC-ζ and glucose uptake. Thus, PED/PEA-15 action on glucose transport is mediated through PKC-α–dependent inhibition of PKC-ζ.","method":"PKC isoform blockade (pharmacological and dominant-negative), 2-deoxyglucose uptake assay, PKC-ζ activity measurement in L6(PED) cells","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative kinase plus pharmacological inhibition with functional rescue; single lab","pmids":["11375323"],"is_preprint":false},{"year":2002,"finding":"PEA-15 controls the activity of ERK, JNK, and p38 subfamilies of MAPKs. PED/PEA-15 simultaneously activates ERK1/2 and inhibits JNK/p38 signaling (by impairing Cdc-42, MKK4, MKK6 activation). The anti-apoptotic function of PED requires both ERK activation and JNK/p38 inhibition.","method":"293 cell transfection, kinase phosphorylation assays, MEK inhibitor (PD98059) epistasis, JNK1 and p38 overexpression rescue, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple kinase assays with pharmacological and genetic epistasis; single lab","pmids":["11790785"],"is_preprint":false},{"year":2002,"finding":"The three-dimensional structure of PEA-15 was determined by NMR spectroscopy: PEA-15 consists of an N-terminal death effector domain (DED) and a C-terminal tail of irregular structure. NMR footprinting and mutagenesis identified residues in both the DED and C-terminal tail required for ERK binding. The DED surface used by PEA-15 to bind ERK2 is similar to the death domain (DD) surface used by Drosophila Tube, revealing an unexpected common docking mode.","method":"NMR structure determination, NMR chemical shift footprinting, site-directed mutagenesis of ERK-binding residues","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation by mutagenesis; rigorous single-study with multiple orthogonal methods","pmids":["12456656"],"is_preprint":false},{"year":2002,"finding":"Only the doubly phosphorylated form of PED/PEA-15 is recruited to the TRAIL death-inducing signaling complex (DISC) in TRAIL-resistant glioma cells. CaMK inhibitor treatment rescues TRAIL sensitivity, indicating that CaMK-dependent phosphorylation of PEA-15 is required for its DISC recruitment and TRAIL resistance.","method":"DISC immunoprecipitation from TRAIL-sensitive and -resistant glioma cells, Western blot with phospho-specific antibodies, CaMK inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical DISC pull-down distinguishing phosphorylation state plus pharmacological rescue; single lab","pmids":["11976344"],"is_preprint":false},{"year":2003,"finding":"Protein kinase B/Akt directly binds PEA-15 (independently of Akt activity) and phosphorylates it at Ser116. Akt phosphorylation of Ser116 stabilizes PEA-15 by reducing its ubiquitin-dependent proteasomal degradation. A nonphosphorylatable S116G mutant showed 10-fold reduced Akt phosphorylation, a 3-fold higher degradation rate, and ~2-fold reduced anti-apoptotic activity.","method":"In vitro kinase assay with recombinant Akt and PEA-15, phospho-Ser116-specific antibodies, pull-down and co-immunoprecipitation, S116G point mutant, pulse-chase stability assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mutagenesis (S116G), phospho-specific antibody, stability measurement; multiple orthogonal methods","pmids":["12808093"],"is_preprint":false},{"year":2003,"finding":"PEA-15 binds RSK2 (but not RSK1) through its C-terminal tail, not the DED. This interaction inhibits RSK2 kinase activity by ~50%, blocks nuclear accumulation of RSK2 after EGF stimulation, and suppresses RSK2-dependent CREB transcription and histone H3 phosphorylation. PEA-15 does not alter ERK phosphorylation of RSK2 and is not itself an RSK2 substrate.","method":"Co-immunoprecipitation, in vitro binding with translated RSK2, RSK2 kinase assay, nuclear localization imaging, CREB reporter assay, histone H3 phosphorylation assay, C-terminal deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro binding, kinase activity assay, nuclear localization, transcription reporter; multiple orthogonal methods in single study","pmids":["12796492"],"is_preprint":false},{"year":2004,"finding":"PEA-15 prevents nuclear entry of ERK2 by interfering with ERK2–nucleoporin interactions. The MAP kinase insert region of ERK2 is required for both PEA-15 binding and nucleoporin binding. In a permeabilized cell system, excess PEA-15 blocked wild-type ERK2 nuclear entry but not MAP kinase insert-deleted ERK2.","method":"Permeabilized cell nuclear import assay, ERK2/p38 chimeras and MAP kinase insert mutants, nucleoporin binding assay, ERK2 localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted permeabilized cell system plus mutagenesis identifying specific ERK2 domain; multiple orthogonal methods","pmids":["14707138"],"is_preprint":false},{"year":2004,"finding":"Pro-apoptotic Omi/HtrA2 mitochondrial serine protease directly binds the DED of PED/PEA-15 and degrades it. Upon UVC exposure, Omi/HtrA2 is released from mitochondria into the cytoplasm, binds PED/PEA-15, and proteolytically degrades it; specific Omi inhibitor ucf-101 prevents this degradation. PED/PEA-15 in turn blocks Omi/HtrA2 co-precipitation with XIAP, modulating caspase-3 activation.","method":"Yeast two-hybrid screen, in vitro binding and in vitro degradation assay, co-immunoprecipitation, ucf-101 inhibitor treatment, caspase-3 activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast two-hybrid plus in vitro reconstituted degradation assay plus co-IP plus enzymatic inhibitor rescue; multiple orthogonal methods","pmids":["15328349"],"is_preprint":false},{"year":2004,"finding":"High expression of PED/PEA-15 in primitive neural stem/progenitor cells localizes to the death-inducing signaling complex (DISC) and prevents caspase-8 recruitment and activation, providing protection from death receptor–induced apoptosis. Lentiviral antisense knockdown of PED sensitizes these cells to apoptosis by inflammatory cytokines and death receptors.","method":"DISC immunoprecipitation, lentiviral antisense PED knockdown, caspase-8 activation assay, neural stem cell apoptosis assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — DISC pull-down plus lentiviral loss-of-function with defined apoptosis phenotype; clean mechanistic study","pmids":["15545353"],"is_preprint":false},{"year":2004,"finding":"PEA-15 promotes cytoplasmic ERK localization during oncogenic Ras-induced cellular senescence. RNAi-mediated knockdown of PEA-15 in Ras-expressing primary mouse embryo fibroblasts restores nuclear phospho-ERK localization and promotes escape from senescence, indicating PEA-15 acts as a nuclear export factor for ERK1/2 in this context.","method":"RNA interference against PEA-15, ERK localization imaging by immunofluorescence, Ras-induced senescence assay, E1A downregulation of PEA-15 (Western blot)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined localization and phenotypic rescue; single lab","pmids":["15331596"],"is_preprint":false},{"year":2004,"finding":"PED/PEA-15 overexpression in transgenic mice causes diabetes by impairing both insulin action and glucose-stimulated insulin secretion. In muscle and fat, PED overexpression activates PKC-α and blocks insulin induction of PKC-ζ; in beta-cells, it blocks PKC-ζ induction by glucose, reducing expression of Sur1, Kir6.2 potassium channel subunits and their regulator Foxa2.","method":"PED transgenic mice, in vivo glucose/insulin tolerance tests, isolated adipocyte glucose uptake, PKC isoform activity assays, MIN6 beta-cell stable overexpression, antisense knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model plus multiple in vitro and in vivo mechanistic assays; replicated in a subsequent beta-cell-specific transgenic study (PMID 17327429)","pmids":["15143191"],"is_preprint":false},{"year":2005,"finding":"Phosphorylation of PEA-15 at Ser104 blocks ERK binding in vitro and in vivo, whereas phosphorylation at Ser116 promotes FADD binding. These phosphorylation events act as a molecular switch determining whether PEA-15 engages the proliferation (ERK) or apoptosis (FADD) pathway. All phosphorylation states of PEA-15 remain predominantly cytoplasmic, so phosphorylation does not influence nuclear versus cytoplasmic distribution.","method":"In vitro binding assays with phosphomimetic and non-phosphorylatable mutants, co-immunoprecipitation from cells, phospho-epitope antibody characterization, subcellular fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro binding plus in vivo co-IP with multiple phospho-mutants plus cellular fractionation; defined mechanistic switch","pmids":["15916534"],"is_preprint":false},{"year":2005,"finding":"Phosphorylation of both Ser104 and Ser116 is required to block PEA-15 interaction with ERK1/2. Using phosphomimetic and non-phosphorylatable PEA-15 mutants, dual phosphorylation abrogates PEA-15-mediated inhibition of ERK nuclear localization and transcriptional activity, thus enabling cell proliferation. PEA-15 phosphorylation also modulates non-transcriptional ERK effects on integrin activation.","method":"Phosphomimetic (S104D/S116D) and non-phosphorylatable (S104A/S116A) mutants, in vitro binding, ERK nuclear localization assay, Elk-1/cFos reporter assay, integrin activation assay, phospho-specific antibody in situ staining","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — combined phosphomimetic/non-phosphorylatable mutant analysis with multiple functional readouts; agrees with and extends PMID 15916534","pmids":["15917297"],"is_preprint":false},{"year":2003,"finding":"PEA-15 reversal of Raf-1-mediated integrin suppression depends on its capacity to bind ERK1/2. Mutations in either the DED or C-terminal tail that block ERK1/2 binding abolish integrin suppression reversal. ERK1/2 residues preceding the αG helix and within the MAP kinase insert are required for PEA-15 binding and are also required for ERK2 to suppress integrin activation. Membrane-targeted ERK1/2-CAAX suppresses integrin activation in a manner not reversible by PEA-15.","method":"ERK2/p38 chimeras, site-directed mutagenesis of ERK2, membrane-targeted ERK1/2-CAAX constructs, integrin activation assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis of both PEA-15 and ERK2 with integrin activation readout; single lab","pmids":["14506247"],"is_preprint":false},{"year":2007,"finding":"PEA-15 inhibits tumor cell invasion by binding ERK1/2 and preventing their nuclear localization. PEA-15 mutants that cannot bind ERK1/2 fail to inhibit invasion; overexpression of ERK1 or activated MEK reverses PEA-15-mediated invasion inhibition; a PEA-15 mutant that cannot prevent ERK nuclear localization does not inhibit invasion.","method":"shRNA-mediated PEA-15 knockdown, forced overexpression, ERK1/2-binding mutants of PEA-15, ERK1/MEK overexpression rescue, invasion assay, ERK nuclear localization imaging","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants with invasion and localization readouts; single lab","pmids":["17308092"],"is_preprint":false},{"year":2007,"finding":"PEA-15 acts as a scaffold that targets ERK to RSK2 by simultaneously binding both proteins, thereby enhancing ERK-mediated RSK2 activation and CREB transcription. This scaffolding activity is regulated by PEA-15 phosphorylation. In PEA-15-null lymphocytes, phorbol ester-stimulated RSK2 activation is impaired and rescued by exogenous PEA-15.","method":"Co-immunoprecipitation, in vitro binding, RSK2 kinase assay, CREB reporter assay, PEA-15-null lymphocyte rescue experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP and in vitro binding plus kinase assay plus genetic null rescue; multiple orthogonal methods","pmids":["18077417"],"is_preprint":false},{"year":2007,"finding":"PEA-15 is a high-affinity ligand for both ERK1 and ERK2 (Kd ~0.2–0.4 μM regardless of ERK activation state). PEA-15 binds at the D-recruitment site (DRS) of ERK1/2 (likely via its C-terminus) in a bidentate manner also involving the MAP kinase insert. PEA-15 competes with D-site-containing substrates (Elk-1, Ets-1) and potently inhibits ERK2-mediated phosphorylation of these transcription factors. Neither PEA-15 phosphorylation nor ERK1/2 activation state significantly affects binding affinity.","method":"Fluorescence anisotropy binding assay, competition assay with Elk-1 D-site peptide, single-cysteine ERK2 alkylation protection assay, in vitro ERK2 kinase assay with Elk-1 and Ets-1","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding (fluorescence anisotropy), site-directed alkylation protection, and in vitro kinase assay; multiple rigorous methods in one study","pmids":["17658892"],"is_preprint":false},{"year":2007,"finding":"PED/PEA-15 overexpression in pancreatic beta-cells inhibits PKC-ζ induction by glucose, thereby reducing expression of potassium channel subunits Sur1, Kir6.2 and Foxa2 and impairing glucose-stimulated insulin secretion. Rescue of PKC-ζ activity in PED-overexpressing beta-cells restores channel gene expression and insulin secretion. PED/PEA-15-null mouse islets show increased PKC-ζ activation and enhanced insulin secretion.","method":"Beta-cell-specific PED transgenic mice, islet isolation, glucose-stimulated insulin secretion assay, PKC-ζ activity assay, mRNA quantification of Sur1/Kir6.2/Foxa2, MIN-6 and INS-1 cell overexpression/antisense knockdown","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific transgenic plus null mouse plus mechanistic cell-based rescue; multiple orthogonal methods and genetic models","pmids":["17327429"],"is_preprint":false},{"year":2007,"finding":"TPA (phorbol ester) increases PED/PEA-15 cellular levels post-translationally by inducing phosphorylation at Ser116 via a PKC-ζ/CaMKII pathway that prevents ubiquitinylation and proteasomal degradation of PED/PEA-15. The S116G mutant abolishes TPA-mediated protection from ubiquitin-dependent degradation.","method":"Ubiquitin co-immunoprecipitation, proteasome inhibitor (lactacystin) treatment, PKC-ζ dominant-negative and antisense, CaMK inhibitor (KN-93), S116G and S104G mutants, pulse-chase protein stability","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and pharmacological interventions targeting ubiquitination plus mutagenesis; multiple orthogonal methods","pmids":["17227770"],"is_preprint":false},{"year":2008,"finding":"PED/PEA-15 binds the C-terminal D4 domain of PLD1 with high affinity (Kd ~0.37 μM). A peptide spanning PED residues 1–24 competes with this interaction. Disrupting PED/PEA-15–PLD1 binding in L6 skeletal muscle cells overexpressing PED abolishes the PED-induced PKC-α activation and restores insulin-stimulated glucose uptake by ~70%.","method":"Surface plasmon resonance, ELISA-like binding assay, peptide competition in cells and transgenic mouse-derived myocytes, PKC-α activity assay, 2-deoxyglucose uptake assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biophysical binding (SPR) plus functional peptide competition rescue in cells; multiple orthogonal methods","pmids":["18541525"],"is_preprint":false},{"year":2010,"finding":"PEA-15 promotes autophagy in glioma cells in a JNK-dependent manner. Overexpression of PEA-15 potently activates JNK; this activation depends on phosphorylation at both Ser104 and Ser116. JNK inhibition abrogates PEA-15-mediated autophagy induction. Non-phosphorylatable PEA-15 mutants fail to promote autophagy.","method":"PEA-15 overexpression in glioma cells, siRNA knockdown, JNK phosphorylation assay, autophagy markers (LC3), JNK inhibitor treatment, phosphorylation-site mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and RNAi plus pharmacological epistasis with JNK inhibitor plus phospho-mutants; single lab","pmids":["20452983"],"is_preprint":false},{"year":2011,"finding":"Activated ERK2 forms a 1:1 monomeric complex with PEA-15 (~57 kDa by light scattering); ERK2 itself does not dimerize under physiological conditions with or without divalent cations. This confirms the PEA-15–ERK2 interaction is a 1:1 stoichiometric complex.","method":"Static light scattering, analytical ultracentrifugation (sedimentation equilibrium and velocity), dynamic light scattering, NMR diffusion measurement","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple quantitative biophysical methods (light scattering, AUC, NMR) establishing stoichiometry; rigorous single study","pmids":["21506533"],"is_preprint":false},{"year":2011,"finding":"Hsp27 regulates PEA-15 activity through Akt: Hsp27 silencing decreases Akt-mediated phosphorylation of PEA-15, causing PEA-15 to bind and sequester ERK (inhibiting proliferation) while releasing FADD (enabling Fas-induced apoptosis). Hsp27 overexpression promotes proliferation and suppresses Fas-induced apoptosis via the same PEA-15 molecular switch.","method":"Hsp27 siRNA silencing and overexpression, Akt inhibition, co-immunoprecipitation of PEA-15 with ERK and FADD, ERK nuclear localization assay, Fas-induced apoptosis assay, cell proliferation assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing PEA-15 binding switch plus localization and apoptosis readouts; single lab, but consistent with established PEA-15 mechanism","pmids":["22179576"],"is_preprint":false},{"year":2012,"finding":"Hexokinase II (HKII) directly interacts with PEA-15 and together they inhibit apoptosis after hypoxia. Under glucose deprivation (normoxia), HKII accelerates apoptosis in the absence of PEA-15, demonstrating that HKII acts as a metabolic sensor and that its pro-survival vs. pro-apoptotic output is gated by PEA-15.","method":"Co-immunoprecipitation of HKII and PEA-15, siRNA knockdown of PEA-15, hypoxia/glucose deprivation apoptosis assays, HKII overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic knockdown with defined metabolic and apoptotic phenotypes; single lab","pmids":["22233811"],"is_preprint":false},{"year":2012,"finding":"PED/PEA-15 induces autophagy and mediates TGF-β1-driven inhibition of skeletal muscle cell differentiation through a PP2A/FoxO1 mechanism. TGF-β1 transcriptionally upregulates PED/PEA-15; specific PED/PEA-15 shRNAs block both TGF-β1-induced autophagy and impaired differentiation. PED/PEA-15 overexpressing transgenic mice show atrophic muscle fibers with increased LC3II/LC3I and reduced PP2A/FoxO1 phosphorylation.","method":"TGF-β1 treatment of myoblasts, PED/PEA-15 shRNA, autophagy inhibitor (3-methyladenine), transgenic mouse muscle analysis (LC3, FoxO1 phosphorylation), myotube differentiation assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic shRNA with functional rescue plus transgenic mouse confirmation; single lab","pmids":["22281705"],"is_preprint":false},{"year":2012,"finding":"PED/PEA-15 interacts with the 67 kDa laminin receptor (67LR/37LRP). This interaction was confirmed by yeast two-hybrid, pull-down with recombinant His-tagged 37LRP, and co-immunoprecipitation. 67LR-mediated laminin signaling induces phosphorylation of PED/PEA-15 at both Ser104 and Ser116, enabling cell proliferation and apoptosis resistance.","method":"Yeast two-hybrid screen, recombinant His-tag pull-down, co-immunoprecipitation, cell adhesion/migration assay on laminin, phospho-specific Western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus pull-down plus co-IP; multiple binding assays but no mutagenesis or reconstitution; single lab","pmids":["21895963"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of PEA-15 bound to three different ERK2 phospho-conformers reveal a bipartite binding mode: PEA-15 occupies both the D-recruitment site (DRS) and the DEF-binding site (DBS) of ERK2. PEA-15 can bind the ERK2 activation loop in the Thr-X-Tyr region in different phosphorylation states. Dually phosphorylated ERK2 bound by PEA-15 undergoes allosteric disruption of active-conformation features, while PEA-15 protects ERK2 from dephosphorylation.","method":"X-ray crystallography of PEA-15/ERK2 complexes in three phospho-conformations, structural analysis of allosteric changes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of multiple phospho-conformer complexes with structural mechanistic analysis; highest-tier evidence","pmids":["23575685"],"is_preprint":false},{"year":2014,"finding":"AMPK directly phosphorylates PEA-15 at Ser116. In mammary cells forming mammospheres, AMPK activity increases and phosphorylates PEA-15 at Ser116, promoting its anti-apoptotic function. AMPK or PEA-15 knockdown, or overexpression of the non-phosphorylatable S116A PEA-15 mutant, impairs mammosphere formation and anoikis resistance.","method":"In vitro AMPK kinase assay with PEA-15 substrate, immunoprecipitation of AMPK-PEA-15 complex, shRNA knockdown, S116A PEA-15 mutant overexpression, mammosphere and xenograft assays","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus co-IP plus mutagenesis (S116A) with functional readout; multiple orthogonal methods","pmids":["25096718"],"is_preprint":false},{"year":2014,"finding":"PED/PEA-15 is degraded via chaperone-mediated autophagy (CMA) through interaction with HSC70. PED has two KFERQ-like CMA targeting motifs; phosphorylation at the motif overlapping a phosphorylation site prevents HSC70 from accessing it, thus blocking CMA-mediated degradation. Unphosphorylated PED is preferentially targeted by HSC70 to lysosomes.","method":"Tandem affinity purification identifying HSC70 as PED interactor, CMA substrate assay, KFERQ motif mutagenesis, lysosomal fractionation, phospho-mimetic and non-phosphorylatable PED mutants","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP identification plus CMA assay plus mutant analysis; single lab but multiple methods","pmids":["24477641"],"is_preprint":false},{"year":2011,"finding":"PEA-15 potentiates H-Ras-mediated epithelial cell transformation through activation of its binding partner PLD1. In H-Ras-transformed cells, PEA-15 co-expression enhances ERK activation, G1/S cell cycle progression, anchorage-independent growth and tumor growth in vivo. Inhibition of PLD1 or disruption of PEA-15/PLD1 binding blocks these PEA-15-mediated oncogenic effects.","method":"Soft agar colony formation, in vivo tumor xenograft, PLD1 inhibition, PEA-15/PLD1 binding interference, ERK activity assay, cell cycle analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with pharmacological and binding-site-disruption epistasis; single lab","pmids":["22105357"],"is_preprint":false},{"year":2010,"finding":"PED/PEA-15 interacts with Rac1 GTPase and facilitates AKT-mediated Rac1-Ser71 phosphorylation. Constitutively active Rac affects PED-Ser104 phosphorylation. PED augments migration and invasion in NSCLC cells in a Rac1-dependent manner, with effects mediated through the ERK1/2 pathway.","method":"Tandem affinity purification (TAP) identifying Rac1, co-immunoprecipitation, Rac1 siRNA and pharmacological inhibition, migration/invasion assay, phosphorylation analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP plus co-IP plus RNAi plus functional migration assay; single lab","pmids":["20648624"],"is_preprint":false},{"year":2012,"finding":"PED/PEA-15 overexpression in fibroblasts impairs cell motility and wound closure through ERK1/2-dependent suppression of RhoA activation. TgPED fibroblasts show increased phospho-ERK1/2, decreased RhoA activation, reduced stress fibers and focal adhesions. ERK1/2 inhibition (PD98059) rescues RhoA activation and restores motility. PED-null fibroblasts show accelerated wound closure in vitro and in vivo.","method":"Transgenic and knockout mouse fibroblasts, scratch wound assay, time-lapse migration, RhoA activation assay, ERK inhibitor rescue, in vivo dorsal wound healing","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic + KO genetic models with pharmacological ERK epistasis and defined motility phenotype; single lab","pmids":["21780113"],"is_preprint":false},{"year":2015,"finding":"PEA-15 is under integrin α5β1/AKT control. Inhibition of α5β1 integrin decreases PEA-15 levels, which in turn activates the p53 pathway to repress survivin; conversely, survivin repression decreases α5β1 integrin expression. This interconnection creates a pro-apoptotic loop in glioma cells.","method":"siRNA knockdown of PEA-15 and survivin, integrin-blocking antibodies and RGD antagonists, Western blot, caspase-8/3 activity assay, Nutlin-3a treatment","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with multiple interactors and apoptotic readouts; single lab","pmids":["26470725"],"is_preprint":false},{"year":2022,"finding":"DUSP7 (dual specificity phosphatase 7), transcriptionally induced by FOSL1, directly dephosphorylates PEA15. FOSL1 promotes drug resistance in breast cancer through DUSP7-mediated dephosphorylation of PEA15, shifting PEA15 from tumor-suppressor to pro-survival function.","method":"qRT-PCR, ChIP for FOSL1 binding to DUSP7 promoter, siRNA knockdown of FOSL1/DUSP7, Western blot of phospho-PEA15, doxorubicin resistance assays in vitro and in vivo","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus siRNA epistasis plus phospho-Western documenting dephosphorylation; single lab","pmids":["34907034"],"is_preprint":false}],"current_model":"PEA-15 (PED/PEA-15) is a 15 kDa cytoplasmic adapter protein with an N-terminal death effector domain (DED) that functions as a dual regulator of cell proliferation and apoptosis: it sequesters ERK1/2 in the cytoplasm by binding two sites on ERK2 (the D-recruitment site and MAP kinase insert region), thereby blocking ERK nuclear translocation, transcription, and proliferation, while also engaging a scaffold role to target ERK toward RSK2; it inhibits extrinsic apoptosis by binding FADD and caspase-8 at the DISC, blocking their activation; and it regulates glucose metabolism by interacting with PLD1 to activate PKC-α, which inhibits PKC-ζ and impairs insulin-stimulated GLUT4 recruitment. Its activities are tightly controlled by phosphorylation: PKC phosphorylates Ser104 (blocking ERK binding), and CaMKII, Akt, or AMPK phosphorylate Ser116 (promoting FADD binding, stabilizing the protein against ubiquitin-mediated degradation, and enabling anti-apoptotic function), whereas DUSP7 dephosphorylates PEA-15 to shift its output. Structural studies by NMR and crystallography have defined these interaction interfaces at atomic resolution."},"narrative":{"mechanistic_narrative":"PEA-15 (PED/PEA-15) is a small cytoplasmic death effector domain (DED) adapter that acts as a phosphorylation-gated hub coordinating MAP kinase signaling, apoptosis, and glucose metabolism [PMID:11702783, PMID:15916534]. Through its DED and C-terminal tail it is a high-affinity bidentate ligand of ERK1/2, engaging the D-recruitment site together with the MAP kinase insert region to form a 1:1 complex; this anchors ERK in the cytoplasm via a nuclear export sequence, blocks ERK–nucleoporin interactions and nuclear entry, competes with D-site substrates such as Elk-1 and Ets-1, and protects bound ERK2 from dephosphorylation [PMID:11702783, PMID:14707138, PMID:17658892, PMID:21506533, PMID:23575685]. Loss of PEA-15 raises nuclear phospho-ERK, cFos transcription and proliferation, and PEA-15 restrains tumor cell invasion and Ras-induced senescence escape through this ERK-tethering activity [PMID:11702783, PMID:15331596, PMID:17308092]. PEA-15 also scaffolds ERK onto RSK2 to control CREB-dependent transcription [PMID:12796492, PMID:18077417]. In parallel, the DED binds FADD and caspase-8, displacing their interaction at the death-inducing signaling complex to block extrinsic (TNFα, FasL, TRAIL) apoptosis, a function confirmed by increased death of PEA-15-null astrocytes [PMID:10442631, PMID:10493725, PMID:15545353]. In metabolism, PEA-15 binds the C-terminal D4 domain of PLD1, driving constitutive PKC-α activation that inhibits insulin-responsive PKC-ζ and impairs GLUT4 recruitment and glucose uptake; transgenic overexpression causes diabetes by impairing both insulin action and glucose-stimulated insulin secretion [PMID:9670003, PMID:11375323, PMID:18541525, PMID:15143191, PMID:17327429]. These outputs are switched by phosphorylation: PKC phosphorylates Ser104 to block ERK binding, while CaMKII, Akt, or AMPK phosphorylate Ser116 to promote FADD binding, anti-apoptotic function, and stabilization against ubiquitin- and chaperone-mediated degradation, and DUSP7 dephosphorylation reverses this switch [PMID:8449955, PMID:9721757, PMID:12808093, PMID:15916534, PMID:25096718, PMID:24477641, PMID:34907034].","teleology":[{"year":1993,"claim":"Established PEA-15 as a defined PKC phosphoprotein, providing the first regulatory handle before any function was known.","evidence":"In vitro kinase assay with purified PKC, 2D phosphopeptide mapping in astrocytes","pmids":["8449955"],"confidence":"High","gaps":["Functional consequence of PKC phosphorylation not yet defined","Site not yet mapped to Ser104"]},{"year":1998,"claim":"Identified a second, CaMKII-targeted site (Ser116) distinct from the PKC site, revealing dual-site control of PEA-15.","evidence":"Phosphopeptide microsequencing from endothelin-treated astrocytes plus in vitro CaMKII assay","pmids":["9721757"],"confidence":"High","gaps":["Downstream effect of each site on partner binding not yet established"]},{"year":1998,"claim":"Connected PEA-15 to glucose metabolism, showing it inhibits insulin-stimulated glucose transport upstream of PKC.","evidence":"Stable overexpression in L6 muscle cells, glucose transport/GLUT4 assays with PKC inhibitor rescue","pmids":["9670003"],"confidence":"High","gaps":["Direct PEA-15 binding partner mediating PKC activation not yet identified","In vivo relevance not yet tested"]},{"year":1999,"claim":"Defined the anti-apoptotic mechanism: PEA-15 DED binds FADD and caspase-8 to disrupt DISC assembly, and genetic loss sensitizes cells to death.","evidence":"Reciprocal co-IP in MCF-7/HeLa, PARP cleavage assays, and PEA-15-null astrocyte survival assays","pmids":["10442631","10493725"],"confidence":"High","gaps":["Phosphorylation dependence of FADD binding not yet resolved"]},{"year":2001,"claim":"Established the canonical ERK-sequestration function: PEA-15 anchors ERK1/2 in the cytoplasm via a nuclear export sequence to restrain transcription and proliferation.","evidence":"PEA-15 knockout cells, NES mutant, ERK localization imaging, cFos reporter and proliferation assays","pmids":["11702783"],"confidence":"High","gaps":["Molecular basis of ERK binding interface not yet defined","Mechanism of nuclear-entry blockade unresolved"]},{"year":2002,"claim":"Solved the PEA-15 structure and mapped ERK-binding residues, revealing a DED docking mode shared with death domains.","evidence":"NMR structure determination, chemical-shift footprinting, ERK-binding mutagenesis","pmids":["12456656"],"confidence":"High","gaps":["Atomic detail of the bound ERK2 complex not yet available"]},{"year":2003,"claim":"Identified Akt as a direct Ser116 kinase that stabilizes PEA-15 against proteasomal degradation, coupling survival signaling to protein abundance.","evidence":"In vitro Akt kinase assay, S116G mutant, pulse-chase stability, phospho-specific antibody","pmids":["12808093"],"confidence":"High","gaps":["E3 ligase mediating ubiquitination not identified"]},{"year":2004,"claim":"Resolved the nuclear-entry blockade mechanism: PEA-15 and nucleoporins compete for the ERK2 MAP kinase insert region.","evidence":"Permeabilized-cell nuclear import assay with ERK2 insert mutants and nucleoporin binding assays","pmids":["14707138"],"confidence":"High","gaps":["Whether this fully accounts for cytoplasmic retention versus NES-mediated export not delineated"]},{"year":2007,"claim":"Quantified PEA-15 as a high-affinity bidentate ERK ligand at the D-recruitment site that competes with D-site substrates, explaining transcriptional inhibition.","evidence":"Fluorescence anisotropy binding, alkylation protection, in vitro kinase competition with Elk-1/Ets-1","pmids":["17658892"],"confidence":"High","gaps":["Structural basis of the bidentate mode not yet visualized"]},{"year":2007,"claim":"Reframed PEA-15 as a positive ERK scaffold that targets ERK to RSK2, showing it both sequesters and routes ERK.","evidence":"Co-IP, in vitro binding, RSK2 kinase and CREB reporter assays, PEA-15-null lymphocyte rescue","pmids":["18077417","12796492"],"confidence":"High","gaps":["How phosphorylation toggles between sequestration and scaffolding not fully resolved"]},{"year":2007,"claim":"Defined the metabolic mechanism in vivo and at the binding level: PED/PEA-15 binds the PLD1 D4 domain to drive PKC-α–dependent PKC-ζ inhibition, causing diabetes.","evidence":"SPR binding, peptide competition rescue, PED transgenic and null mice, islet GSIS and PKC isoform assays","pmids":["18541525","15143191","17327429","11375323"],"confidence":"High","gaps":["Detailed signaling between PLD1 binding and PKC-α activation not fully mapped"]},{"year":2005,"claim":"Articulated the phosphorylation switch: Ser104 phosphorylation blocks ERK binding while Ser116 promotes FADD binding, partitioning PEA-15 between proliferation and apoptosis without changing its cytoplasmic distribution.","evidence":"Phosphomimetic/non-phosphorylatable mutants, in vitro binding, co-IP, fractionation, ERK reporter and integrin assays","pmids":["15916534","15917297"],"confidence":"High","gaps":["Spatiotemporal coordination of the two kinases in vivo not resolved"]},{"year":2013,"claim":"Provided atomic-resolution insight into ERK regulation: PEA-15 occupies both the D-recruitment and DEF-binding sites, allosterically disrupting active ERK2 and shielding it from dephosphorylation.","evidence":"X-ray crystallography of PEA-15/ERK2 in three phospho-conformations; stoichiometry by light scattering/AUC","pmids":["23575685","21506533"],"confidence":"High","gaps":["How allosteric inhibition reconciles with protection from dephosphorylation mechanistically not fully explained"]},{"year":2014,"claim":"Extended kinase control to AMPK and revealed chaperone-mediated autophagy as a second degradation route gated by phosphorylation.","evidence":"In vitro AMPK kinase assay and S116A mutant in mammospheres; TAP/HSC70 CMA substrate and KFERQ-motif mutagenesis","pmids":["25096718","24477641"],"confidence":"High","gaps":["Relative contributions of proteasomal versus CMA turnover in vivo not quantified"]},{"year":2022,"claim":"Identified DUSP7 as the phosphatase reversing the PEA-15 switch, linking it to drug-resistance signaling downstream of FOSL1.","evidence":"ChIP, siRNA epistasis, phospho-PEA15 Western blot, doxorubicin resistance assays","pmids":["34907034"],"confidence":"Medium","gaps":["Single lab; site specificity of DUSP7 dephosphorylation not mapped","Direct phosphatase–substrate contact not structurally defined"]},{"year":null,"claim":"How the competing PEA-15 outputs (ERK sequestration vs. RSK2/PLD1 scaffolding vs. DISC inhibition) are spatially and temporally integrated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how a single low-abundance adapter partitions among mutually exclusive partner pools","Endogenous stoichiometry of PEA-15 versus ERK, FADD and PLD1 not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,20,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,14,25,35]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,15,25]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,25,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,5,17]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,9,19,26]}],"complexes":["death-inducing signaling complex (DISC)"],"partners":["MAPK1","FADD","CASP8","PLD1","RPS6KA3","AKT1","PRKAA1","DUSP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15121","full_name":"Astrocytic phosphoprotein PEA-15","aliases":["15 kDa phosphoprotein enriched in astrocytes","Phosphoprotein enriched in diabetes","PED"],"length_aa":130,"mass_kda":15.0,"function":"Blocks Ras-mediated inhibition of integrin activation and modulates the ERK MAP kinase cascade. Inhibits RPS6KA3 activities by retaining it in the cytoplasm (By similarity). Inhibits both TNFRSF6- and TNFRSF1A-mediated CASP8 activity and apoptosis. Regulates glucose transport by controlling both the content of SLC2A1 glucose transporters on the plasma membrane and the insulin-dependent trafficking of SLC2A4 from the cell interior to the surface","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q15121/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEA15","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEA15","total_profiled":1310},"omim":[{"mim_id":"606441","title":"HTRA SERINE PEPTIDASE 2; HTRA2","url":"https://www.omim.org/entry/606441"},{"mim_id":"603434","title":"PROLIFERATION AND APOPTOSIS ADAPTOR PROTEIN 15; PEA15","url":"https://www.omim.org/entry/603434"},{"mim_id":"601763","title":"CASPASE 8, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP8","url":"https://www.omim.org/entry/601763"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":1945.8}],"url":"https://www.proteinatlas.org/search/PEA15"},"hgnc":{"alias_symbol":["HMAT1","MAT1","PED","PEA-15","MAT1H","HUMMAT1H","PED-PEA15","PED/PEA15"],"prev_symbol":[]},"alphafold":{"accession":"Q15121","domains":[{"cath_id":"1.10.533.10","chopping":"1-91","consensus_level":"medium","plddt":85.5763,"start":1,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15121","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15121-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15121-F1-predicted_aligned_error_v6.png","plddt_mean":77.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEA15","jax_strain_url":"https://www.jax.org/strain/search?query=PEA15"},"sequence":{"accession":"Q15121","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15121.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15121/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15121"}},"corpus_meta":[{"pmid":"11702783","id":"PMC_11702783","title":"PEA-15 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DUSP7-Mediated Dephosphorylation of PEA15.","date":"2022","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/34907034","citation_count":23,"is_preprint":false},{"pmid":"9746747","id":"PMC_9746747","title":"Differential expression of Ped gene candidates in preimplantation mouse embryos.","date":"1998","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/9746747","citation_count":23,"is_preprint":false},{"pmid":"17227770","id":"PMC_17227770","title":"Phorbol esters induce intracellular accumulation of the anti-apoptotic protein PED/PEA-15 by preventing ubiquitinylation and proteasomal degradation.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17227770","citation_count":23,"is_preprint":false},{"pmid":"23552738","id":"PMC_23552738","title":"PEA-15 unphosphorylated at both serine 104 and serine 116 inhibits ovarian cancer cell tumorigenicity and progression through blocking 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In vitro phosphorylation by purified PKC occurs at a consensus site (LTRIPSAKK), and two-dimensional peptide mapping confirmed the same site is phosphorylated in intact cells. PKC mediates the transition from the less acidic (Pa) to the more acidic (Pb) isoelectric form of PEA-15.\",\n      \"method\": \"In vitro kinase assay with purified PKC, 2D gel electrophoresis, 2D phosphopeptide mapping, partial microsequencing, [32P] labeling of intact astrocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified PKC plus in-cell phosphopeptide mapping confirming identical site; replicated across multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"8449955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Endothelin-1 stimulation of astrocytes induces phosphorylation of PEA-15 at two distinct sites: Ser104 (the previously identified PKC site) and a novel site Ser116, phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) but not by casein kinase II. CaMKII phosphorylation of Ser116 in vitro facilitates subsequent PKC phosphorylation at Ser104.\",\n      \"method\": \"Microsequencing of phosphopeptides from endothelin-treated astrocytes, in vitro kinase assay with partly purified CaMKII, 2D phosphopeptide mapping, okadaic acid treatment\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphosite identification by microsequencing combined with in vitro CaMKII kinase assay and in-cell 2D phosphopeptide mapping; multiple orthogonal methods in one study\",\n      \"pmids\": [\"9721757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PEA-15 overexpression in L6 skeletal muscle cells increases plasma membrane GLUT1 content and inhibits insulin-stimulated glucose transport and cell-surface GLUT4 recruitment. These effects are reversed by PKC inhibition, placing PEA-15 upstream of PKC in glucose transport regulation.\",\n      \"method\": \"Stable transfection of L6 cells, glucose transport assay, surface GLUT4 measurement, PKC inhibitor rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean overexpression with defined functional readout (glucose uptake, GLUT4 surface levels) plus pharmacological epistasis; independently replicated in subsequent transgenic mouse work\",\n      \"pmids\": [\"9670003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The death effector domain (DED) of PEA-15 is required for its ability to block Ras-mediated suppression of integrin activation. PEA-15 acts through a pathway involving the small GTPase R-Ras (blocked by dominant-negative R-Ras) rather than by blocking ERK MAP kinase activation downstream of Ras.\",\n      \"method\": \"Expression cloning, dominant-negative R-Ras rescue, integrin activation assay, DED deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with dominant-negative R-Ras plus DED mutant, single lab\",\n      \"pmids\": [\"9852038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PEA-15 binds to FADD and FLICE (caspase-8) through its death effector domain, displacing FADD-FLICE interaction and thereby blocking TNFα- and FasL-induced apoptosis. Overexpression of a FADD DED-deletion mutant blocked PEA-15–FLICE association, and TNFα reduced PEA-15 association with endogenous FADD and FLICE.\",\n      \"method\": \"Co-immunoprecipitation from MCF-7 and HeLa cell lysates, PARP cleavage assay for FLICE (caspase-8) activity, DED-deletion mutant FADD overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with multiple interactors plus functional FLICE activation readout and mutant rescue; replicated in independent labs (PMID 10493725)\",\n      \"pmids\": [\"10442631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PEA-15 knockout in mice demonstrates that endogenous PEA-15 expression protects astrocytes from TNFα-induced apoptosis in vitro. PEA-15 null astrocytes show increased death after TNFα exposure, and in vitro assays confirm PEA-15 binding to FADD and caspase-8 as the mechanistic basis.\",\n      \"method\": \"PEA-15 null mutant mouse generation, in vitro astrocyte apoptosis assay, in vitro binding assays for FADD and caspase-8\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype (astrocyte survival) plus direct binding assay; independent confirmation of PMID 10442631\",\n      \"pmids\": [\"10493725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PEA-15 activates the ERK MAP kinase pathway in a Ras-dependent manner: PEA-15 expression in CHO cells increases Ras GTP loading, MEK and ERK activity, and bypasses the anchorage-dependence of ERK activation. The DED of PEA-15 is required for this ERK-activating function.\",\n      \"method\": \"ERK/MEK kinase assays, Ras-GTP pull-down, anchorage-independent ERK activation assay, DED deletion mutant analysis in CHO cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (Ras-GTP loading, kinase activity) with DED mutant; single lab\",\n      \"pmids\": [\"10982386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PEA-15 interacts with phospholipase D1 (PLD1) and PLD2. The PLD1-interacting site on PEA-15 encompasses part of the DED plus C-terminal flanking sequences, overlapping the RhoA-interacting site on PLD1. PEA-15 co-expression increases PLD1 protein expression levels (faster accumulation, longer persistence) without directly affecting PLD1 enzymatic activity, suggesting PEA-15 acts as a PLD chaperone/stabilizer.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro PLD activity assay, co-expression stability analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus in vitro activity assay; single lab\",\n      \"pmids\": [\"10926929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PEA-15 mediates cytoplasmic sequestration of ERK1/2 MAP kinases by binding ERKs and preventing their nuclear localization. PEA-15 contains a nuclear export sequence required for cytoplasmic ERK anchoring. Genetic deletion of PEA-15 results in increased ERK nuclear localization, increased cFos transcription, and increased cell proliferation.\",\n      \"method\": \"PEA-15 knockout mouse cells, nuclear export sequence mutant, ERK localization imaging, cFos reporter assay, cell proliferation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined localization and transcriptional phenotype, plus nuclear export sequence mutant; replicated in multiple subsequent studies\",\n      \"pmids\": [\"11702783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In L6 skeletal muscle cells overexpressing PED/PEA-15, PKC-α and PKC-β are constitutively activated and inhibit PKC-ζ insulin responsiveness. Blockade of PKC-α (more effectively than PKC-β) restores insulin activation of PKC-ζ and glucose uptake. Thus, PED/PEA-15 action on glucose transport is mediated through PKC-α–dependent inhibition of PKC-ζ.\",\n      \"method\": \"PKC isoform blockade (pharmacological and dominant-negative), 2-deoxyglucose uptake assay, PKC-ζ activity measurement in L6(PED) cells\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative kinase plus pharmacological inhibition with functional rescue; single lab\",\n      \"pmids\": [\"11375323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PEA-15 controls the activity of ERK, JNK, and p38 subfamilies of MAPKs. PED/PEA-15 simultaneously activates ERK1/2 and inhibits JNK/p38 signaling (by impairing Cdc-42, MKK4, MKK6 activation). The anti-apoptotic function of PED requires both ERK activation and JNK/p38 inhibition.\",\n      \"method\": \"293 cell transfection, kinase phosphorylation assays, MEK inhibitor (PD98059) epistasis, JNK1 and p38 overexpression rescue, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple kinase assays with pharmacological and genetic epistasis; single lab\",\n      \"pmids\": [\"11790785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The three-dimensional structure of PEA-15 was determined by NMR spectroscopy: PEA-15 consists of an N-terminal death effector domain (DED) and a C-terminal tail of irregular structure. NMR footprinting and mutagenesis identified residues in both the DED and C-terminal tail required for ERK binding. The DED surface used by PEA-15 to bind ERK2 is similar to the death domain (DD) surface used by Drosophila Tube, revealing an unexpected common docking mode.\",\n      \"method\": \"NMR structure determination, NMR chemical shift footprinting, site-directed mutagenesis of ERK-binding residues\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation by mutagenesis; rigorous single-study with multiple orthogonal methods\",\n      \"pmids\": [\"12456656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Only the doubly phosphorylated form of PED/PEA-15 is recruited to the TRAIL death-inducing signaling complex (DISC) in TRAIL-resistant glioma cells. CaMK inhibitor treatment rescues TRAIL sensitivity, indicating that CaMK-dependent phosphorylation of PEA-15 is required for its DISC recruitment and TRAIL resistance.\",\n      \"method\": \"DISC immunoprecipitation from TRAIL-sensitive and -resistant glioma cells, Western blot with phospho-specific antibodies, CaMK inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical DISC pull-down distinguishing phosphorylation state plus pharmacological rescue; single lab\",\n      \"pmids\": [\"11976344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Protein kinase B/Akt directly binds PEA-15 (independently of Akt activity) and phosphorylates it at Ser116. Akt phosphorylation of Ser116 stabilizes PEA-15 by reducing its ubiquitin-dependent proteasomal degradation. A nonphosphorylatable S116G mutant showed 10-fold reduced Akt phosphorylation, a 3-fold higher degradation rate, and ~2-fold reduced anti-apoptotic activity.\",\n      \"method\": \"In vitro kinase assay with recombinant Akt and PEA-15, phospho-Ser116-specific antibodies, pull-down and co-immunoprecipitation, S116G point mutant, pulse-chase stability assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mutagenesis (S116G), phospho-specific antibody, stability measurement; multiple orthogonal methods\",\n      \"pmids\": [\"12808093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PEA-15 binds RSK2 (but not RSK1) through its C-terminal tail, not the DED. This interaction inhibits RSK2 kinase activity by ~50%, blocks nuclear accumulation of RSK2 after EGF stimulation, and suppresses RSK2-dependent CREB transcription and histone H3 phosphorylation. PEA-15 does not alter ERK phosphorylation of RSK2 and is not itself an RSK2 substrate.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding with translated RSK2, RSK2 kinase assay, nuclear localization imaging, CREB reporter assay, histone H3 phosphorylation assay, C-terminal deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro binding, kinase activity assay, nuclear localization, transcription reporter; multiple orthogonal methods in single study\",\n      \"pmids\": [\"12796492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PEA-15 prevents nuclear entry of ERK2 by interfering with ERK2–nucleoporin interactions. The MAP kinase insert region of ERK2 is required for both PEA-15 binding and nucleoporin binding. In a permeabilized cell system, excess PEA-15 blocked wild-type ERK2 nuclear entry but not MAP kinase insert-deleted ERK2.\",\n      \"method\": \"Permeabilized cell nuclear import assay, ERK2/p38 chimeras and MAP kinase insert mutants, nucleoporin binding assay, ERK2 localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted permeabilized cell system plus mutagenesis identifying specific ERK2 domain; multiple orthogonal methods\",\n      \"pmids\": [\"14707138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Pro-apoptotic Omi/HtrA2 mitochondrial serine protease directly binds the DED of PED/PEA-15 and degrades it. Upon UVC exposure, Omi/HtrA2 is released from mitochondria into the cytoplasm, binds PED/PEA-15, and proteolytically degrades it; specific Omi inhibitor ucf-101 prevents this degradation. PED/PEA-15 in turn blocks Omi/HtrA2 co-precipitation with XIAP, modulating caspase-3 activation.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding and in vitro degradation assay, co-immunoprecipitation, ucf-101 inhibitor treatment, caspase-3 activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast two-hybrid plus in vitro reconstituted degradation assay plus co-IP plus enzymatic inhibitor rescue; multiple orthogonal methods\",\n      \"pmids\": [\"15328349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"High expression of PED/PEA-15 in primitive neural stem/progenitor cells localizes to the death-inducing signaling complex (DISC) and prevents caspase-8 recruitment and activation, providing protection from death receptor–induced apoptosis. Lentiviral antisense knockdown of PED sensitizes these cells to apoptosis by inflammatory cytokines and death receptors.\",\n      \"method\": \"DISC immunoprecipitation, lentiviral antisense PED knockdown, caspase-8 activation assay, neural stem cell apoptosis assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — DISC pull-down plus lentiviral loss-of-function with defined apoptosis phenotype; clean mechanistic study\",\n      \"pmids\": [\"15545353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PEA-15 promotes cytoplasmic ERK localization during oncogenic Ras-induced cellular senescence. RNAi-mediated knockdown of PEA-15 in Ras-expressing primary mouse embryo fibroblasts restores nuclear phospho-ERK localization and promotes escape from senescence, indicating PEA-15 acts as a nuclear export factor for ERK1/2 in this context.\",\n      \"method\": \"RNA interference against PEA-15, ERK localization imaging by immunofluorescence, Ras-induced senescence assay, E1A downregulation of PEA-15 (Western blot)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined localization and phenotypic rescue; single lab\",\n      \"pmids\": [\"15331596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PED/PEA-15 overexpression in transgenic mice causes diabetes by impairing both insulin action and glucose-stimulated insulin secretion. In muscle and fat, PED overexpression activates PKC-α and blocks insulin induction of PKC-ζ; in beta-cells, it blocks PKC-ζ induction by glucose, reducing expression of Sur1, Kir6.2 potassium channel subunits and their regulator Foxa2.\",\n      \"method\": \"PED transgenic mice, in vivo glucose/insulin tolerance tests, isolated adipocyte glucose uptake, PKC isoform activity assays, MIN6 beta-cell stable overexpression, antisense knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model plus multiple in vitro and in vivo mechanistic assays; replicated in a subsequent beta-cell-specific transgenic study (PMID 17327429)\",\n      \"pmids\": [\"15143191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Phosphorylation of PEA-15 at Ser104 blocks ERK binding in vitro and in vivo, whereas phosphorylation at Ser116 promotes FADD binding. These phosphorylation events act as a molecular switch determining whether PEA-15 engages the proliferation (ERK) or apoptosis (FADD) pathway. All phosphorylation states of PEA-15 remain predominantly cytoplasmic, so phosphorylation does not influence nuclear versus cytoplasmic distribution.\",\n      \"method\": \"In vitro binding assays with phosphomimetic and non-phosphorylatable mutants, co-immunoprecipitation from cells, phospho-epitope antibody characterization, subcellular fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro binding plus in vivo co-IP with multiple phospho-mutants plus cellular fractionation; defined mechanistic switch\",\n      \"pmids\": [\"15916534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Phosphorylation of both Ser104 and Ser116 is required to block PEA-15 interaction with ERK1/2. Using phosphomimetic and non-phosphorylatable PEA-15 mutants, dual phosphorylation abrogates PEA-15-mediated inhibition of ERK nuclear localization and transcriptional activity, thus enabling cell proliferation. PEA-15 phosphorylation also modulates non-transcriptional ERK effects on integrin activation.\",\n      \"method\": \"Phosphomimetic (S104D/S116D) and non-phosphorylatable (S104A/S116A) mutants, in vitro binding, ERK nuclear localization assay, Elk-1/cFos reporter assay, integrin activation assay, phospho-specific antibody in situ staining\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combined phosphomimetic/non-phosphorylatable mutant analysis with multiple functional readouts; agrees with and extends PMID 15916534\",\n      \"pmids\": [\"15917297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PEA-15 reversal of Raf-1-mediated integrin suppression depends on its capacity to bind ERK1/2. Mutations in either the DED or C-terminal tail that block ERK1/2 binding abolish integrin suppression reversal. ERK1/2 residues preceding the αG helix and within the MAP kinase insert are required for PEA-15 binding and are also required for ERK2 to suppress integrin activation. Membrane-targeted ERK1/2-CAAX suppresses integrin activation in a manner not reversible by PEA-15.\",\n      \"method\": \"ERK2/p38 chimeras, site-directed mutagenesis of ERK2, membrane-targeted ERK1/2-CAAX constructs, integrin activation assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis of both PEA-15 and ERK2 with integrin activation readout; single lab\",\n      \"pmids\": [\"14506247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PEA-15 inhibits tumor cell invasion by binding ERK1/2 and preventing their nuclear localization. PEA-15 mutants that cannot bind ERK1/2 fail to inhibit invasion; overexpression of ERK1 or activated MEK reverses PEA-15-mediated invasion inhibition; a PEA-15 mutant that cannot prevent ERK nuclear localization does not inhibit invasion.\",\n      \"method\": \"shRNA-mediated PEA-15 knockdown, forced overexpression, ERK1/2-binding mutants of PEA-15, ERK1/MEK overexpression rescue, invasion assay, ERK nuclear localization imaging\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants with invasion and localization readouts; single lab\",\n      \"pmids\": [\"17308092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PEA-15 acts as a scaffold that targets ERK to RSK2 by simultaneously binding both proteins, thereby enhancing ERK-mediated RSK2 activation and CREB transcription. This scaffolding activity is regulated by PEA-15 phosphorylation. In PEA-15-null lymphocytes, phorbol ester-stimulated RSK2 activation is impaired and rescued by exogenous PEA-15.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, RSK2 kinase assay, CREB reporter assay, PEA-15-null lymphocyte rescue experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP and in vitro binding plus kinase assay plus genetic null rescue; multiple orthogonal methods\",\n      \"pmids\": [\"18077417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PEA-15 is a high-affinity ligand for both ERK1 and ERK2 (Kd ~0.2–0.4 μM regardless of ERK activation state). PEA-15 binds at the D-recruitment site (DRS) of ERK1/2 (likely via its C-terminus) in a bidentate manner also involving the MAP kinase insert. PEA-15 competes with D-site-containing substrates (Elk-1, Ets-1) and potently inhibits ERK2-mediated phosphorylation of these transcription factors. Neither PEA-15 phosphorylation nor ERK1/2 activation state significantly affects binding affinity.\",\n      \"method\": \"Fluorescence anisotropy binding assay, competition assay with Elk-1 D-site peptide, single-cysteine ERK2 alkylation protection assay, in vitro ERK2 kinase assay with Elk-1 and Ets-1\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding (fluorescence anisotropy), site-directed alkylation protection, and in vitro kinase assay; multiple rigorous methods in one study\",\n      \"pmids\": [\"17658892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PED/PEA-15 overexpression in pancreatic beta-cells inhibits PKC-ζ induction by glucose, thereby reducing expression of potassium channel subunits Sur1, Kir6.2 and Foxa2 and impairing glucose-stimulated insulin secretion. Rescue of PKC-ζ activity in PED-overexpressing beta-cells restores channel gene expression and insulin secretion. PED/PEA-15-null mouse islets show increased PKC-ζ activation and enhanced insulin secretion.\",\n      \"method\": \"Beta-cell-specific PED transgenic mice, islet isolation, glucose-stimulated insulin secretion assay, PKC-ζ activity assay, mRNA quantification of Sur1/Kir6.2/Foxa2, MIN-6 and INS-1 cell overexpression/antisense knockdown\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific transgenic plus null mouse plus mechanistic cell-based rescue; multiple orthogonal methods and genetic models\",\n      \"pmids\": [\"17327429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TPA (phorbol ester) increases PED/PEA-15 cellular levels post-translationally by inducing phosphorylation at Ser116 via a PKC-ζ/CaMKII pathway that prevents ubiquitinylation and proteasomal degradation of PED/PEA-15. The S116G mutant abolishes TPA-mediated protection from ubiquitin-dependent degradation.\",\n      \"method\": \"Ubiquitin co-immunoprecipitation, proteasome inhibitor (lactacystin) treatment, PKC-ζ dominant-negative and antisense, CaMK inhibitor (KN-93), S116G and S104G mutants, pulse-chase protein stability\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and pharmacological interventions targeting ubiquitination plus mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"17227770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PED/PEA-15 binds the C-terminal D4 domain of PLD1 with high affinity (Kd ~0.37 μM). A peptide spanning PED residues 1–24 competes with this interaction. Disrupting PED/PEA-15–PLD1 binding in L6 skeletal muscle cells overexpressing PED abolishes the PED-induced PKC-α activation and restores insulin-stimulated glucose uptake by ~70%.\",\n      \"method\": \"Surface plasmon resonance, ELISA-like binding assay, peptide competition in cells and transgenic mouse-derived myocytes, PKC-α activity assay, 2-deoxyglucose uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biophysical binding (SPR) plus functional peptide competition rescue in cells; multiple orthogonal methods\",\n      \"pmids\": [\"18541525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PEA-15 promotes autophagy in glioma cells in a JNK-dependent manner. Overexpression of PEA-15 potently activates JNK; this activation depends on phosphorylation at both Ser104 and Ser116. JNK inhibition abrogates PEA-15-mediated autophagy induction. Non-phosphorylatable PEA-15 mutants fail to promote autophagy.\",\n      \"method\": \"PEA-15 overexpression in glioma cells, siRNA knockdown, JNK phosphorylation assay, autophagy markers (LC3), JNK inhibitor treatment, phosphorylation-site mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and RNAi plus pharmacological epistasis with JNK inhibitor plus phospho-mutants; single lab\",\n      \"pmids\": [\"20452983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Activated ERK2 forms a 1:1 monomeric complex with PEA-15 (~57 kDa by light scattering); ERK2 itself does not dimerize under physiological conditions with or without divalent cations. This confirms the PEA-15–ERK2 interaction is a 1:1 stoichiometric complex.\",\n      \"method\": \"Static light scattering, analytical ultracentrifugation (sedimentation equilibrium and velocity), dynamic light scattering, NMR diffusion measurement\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple quantitative biophysical methods (light scattering, AUC, NMR) establishing stoichiometry; rigorous single study\",\n      \"pmids\": [\"21506533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hsp27 regulates PEA-15 activity through Akt: Hsp27 silencing decreases Akt-mediated phosphorylation of PEA-15, causing PEA-15 to bind and sequester ERK (inhibiting proliferation) while releasing FADD (enabling Fas-induced apoptosis). Hsp27 overexpression promotes proliferation and suppresses Fas-induced apoptosis via the same PEA-15 molecular switch.\",\n      \"method\": \"Hsp27 siRNA silencing and overexpression, Akt inhibition, co-immunoprecipitation of PEA-15 with ERK and FADD, ERK nuclear localization assay, Fas-induced apoptosis assay, cell proliferation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing PEA-15 binding switch plus localization and apoptosis readouts; single lab, but consistent with established PEA-15 mechanism\",\n      \"pmids\": [\"22179576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Hexokinase II (HKII) directly interacts with PEA-15 and together they inhibit apoptosis after hypoxia. Under glucose deprivation (normoxia), HKII accelerates apoptosis in the absence of PEA-15, demonstrating that HKII acts as a metabolic sensor and that its pro-survival vs. pro-apoptotic output is gated by PEA-15.\",\n      \"method\": \"Co-immunoprecipitation of HKII and PEA-15, siRNA knockdown of PEA-15, hypoxia/glucose deprivation apoptosis assays, HKII overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic knockdown with defined metabolic and apoptotic phenotypes; single lab\",\n      \"pmids\": [\"22233811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PED/PEA-15 induces autophagy and mediates TGF-β1-driven inhibition of skeletal muscle cell differentiation through a PP2A/FoxO1 mechanism. TGF-β1 transcriptionally upregulates PED/PEA-15; specific PED/PEA-15 shRNAs block both TGF-β1-induced autophagy and impaired differentiation. PED/PEA-15 overexpressing transgenic mice show atrophic muscle fibers with increased LC3II/LC3I and reduced PP2A/FoxO1 phosphorylation.\",\n      \"method\": \"TGF-β1 treatment of myoblasts, PED/PEA-15 shRNA, autophagy inhibitor (3-methyladenine), transgenic mouse muscle analysis (LC3, FoxO1 phosphorylation), myotube differentiation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic shRNA with functional rescue plus transgenic mouse confirmation; single lab\",\n      \"pmids\": [\"22281705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PED/PEA-15 interacts with the 67 kDa laminin receptor (67LR/37LRP). This interaction was confirmed by yeast two-hybrid, pull-down with recombinant His-tagged 37LRP, and co-immunoprecipitation. 67LR-mediated laminin signaling induces phosphorylation of PED/PEA-15 at both Ser104 and Ser116, enabling cell proliferation and apoptosis resistance.\",\n      \"method\": \"Yeast two-hybrid screen, recombinant His-tag pull-down, co-immunoprecipitation, cell adhesion/migration assay on laminin, phospho-specific Western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus pull-down plus co-IP; multiple binding assays but no mutagenesis or reconstitution; single lab\",\n      \"pmids\": [\"21895963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of PEA-15 bound to three different ERK2 phospho-conformers reveal a bipartite binding mode: PEA-15 occupies both the D-recruitment site (DRS) and the DEF-binding site (DBS) of ERK2. PEA-15 can bind the ERK2 activation loop in the Thr-X-Tyr region in different phosphorylation states. Dually phosphorylated ERK2 bound by PEA-15 undergoes allosteric disruption of active-conformation features, while PEA-15 protects ERK2 from dephosphorylation.\",\n      \"method\": \"X-ray crystallography of PEA-15/ERK2 complexes in three phospho-conformations, structural analysis of allosteric changes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of multiple phospho-conformer complexes with structural mechanistic analysis; highest-tier evidence\",\n      \"pmids\": [\"23575685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AMPK directly phosphorylates PEA-15 at Ser116. In mammary cells forming mammospheres, AMPK activity increases and phosphorylates PEA-15 at Ser116, promoting its anti-apoptotic function. AMPK or PEA-15 knockdown, or overexpression of the non-phosphorylatable S116A PEA-15 mutant, impairs mammosphere formation and anoikis resistance.\",\n      \"method\": \"In vitro AMPK kinase assay with PEA-15 substrate, immunoprecipitation of AMPK-PEA-15 complex, shRNA knockdown, S116A PEA-15 mutant overexpression, mammosphere and xenograft assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus co-IP plus mutagenesis (S116A) with functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"25096718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PED/PEA-15 is degraded via chaperone-mediated autophagy (CMA) through interaction with HSC70. PED has two KFERQ-like CMA targeting motifs; phosphorylation at the motif overlapping a phosphorylation site prevents HSC70 from accessing it, thus blocking CMA-mediated degradation. Unphosphorylated PED is preferentially targeted by HSC70 to lysosomes.\",\n      \"method\": \"Tandem affinity purification identifying HSC70 as PED interactor, CMA substrate assay, KFERQ motif mutagenesis, lysosomal fractionation, phospho-mimetic and non-phosphorylatable PED mutants\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP identification plus CMA assay plus mutant analysis; single lab but multiple methods\",\n      \"pmids\": [\"24477641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PEA-15 potentiates H-Ras-mediated epithelial cell transformation through activation of its binding partner PLD1. In H-Ras-transformed cells, PEA-15 co-expression enhances ERK activation, G1/S cell cycle progression, anchorage-independent growth and tumor growth in vivo. Inhibition of PLD1 or disruption of PEA-15/PLD1 binding blocks these PEA-15-mediated oncogenic effects.\",\n      \"method\": \"Soft agar colony formation, in vivo tumor xenograft, PLD1 inhibition, PEA-15/PLD1 binding interference, ERK activity assay, cell cycle analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with pharmacological and binding-site-disruption epistasis; single lab\",\n      \"pmids\": [\"22105357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PED/PEA-15 interacts with Rac1 GTPase and facilitates AKT-mediated Rac1-Ser71 phosphorylation. Constitutively active Rac affects PED-Ser104 phosphorylation. PED augments migration and invasion in NSCLC cells in a Rac1-dependent manner, with effects mediated through the ERK1/2 pathway.\",\n      \"method\": \"Tandem affinity purification (TAP) identifying Rac1, co-immunoprecipitation, Rac1 siRNA and pharmacological inhibition, migration/invasion assay, phosphorylation analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP plus co-IP plus RNAi plus functional migration assay; single lab\",\n      \"pmids\": [\"20648624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PED/PEA-15 overexpression in fibroblasts impairs cell motility and wound closure through ERK1/2-dependent suppression of RhoA activation. TgPED fibroblasts show increased phospho-ERK1/2, decreased RhoA activation, reduced stress fibers and focal adhesions. ERK1/2 inhibition (PD98059) rescues RhoA activation and restores motility. PED-null fibroblasts show accelerated wound closure in vitro and in vivo.\",\n      \"method\": \"Transgenic and knockout mouse fibroblasts, scratch wound assay, time-lapse migration, RhoA activation assay, ERK inhibitor rescue, in vivo dorsal wound healing\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic + KO genetic models with pharmacological ERK epistasis and defined motility phenotype; single lab\",\n      \"pmids\": [\"21780113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PEA-15 is under integrin α5β1/AKT control. Inhibition of α5β1 integrin decreases PEA-15 levels, which in turn activates the p53 pathway to repress survivin; conversely, survivin repression decreases α5β1 integrin expression. This interconnection creates a pro-apoptotic loop in glioma cells.\",\n      \"method\": \"siRNA knockdown of PEA-15 and survivin, integrin-blocking antibodies and RGD antagonists, Western blot, caspase-8/3 activity assay, Nutlin-3a treatment\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with multiple interactors and apoptotic readouts; single lab\",\n      \"pmids\": [\"26470725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DUSP7 (dual specificity phosphatase 7), transcriptionally induced by FOSL1, directly dephosphorylates PEA15. FOSL1 promotes drug resistance in breast cancer through DUSP7-mediated dephosphorylation of PEA15, shifting PEA15 from tumor-suppressor to pro-survival function.\",\n      \"method\": \"qRT-PCR, ChIP for FOSL1 binding to DUSP7 promoter, siRNA knockdown of FOSL1/DUSP7, Western blot of phospho-PEA15, doxorubicin resistance assays in vitro and in vivo\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus siRNA epistasis plus phospho-Western documenting dephosphorylation; single lab\",\n      \"pmids\": [\"34907034\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEA-15 (PED/PEA-15) is a 15 kDa cytoplasmic adapter protein with an N-terminal death effector domain (DED) that functions as a dual regulator of cell proliferation and apoptosis: it sequesters ERK1/2 in the cytoplasm by binding two sites on ERK2 (the D-recruitment site and MAP kinase insert region), thereby blocking ERK nuclear translocation, transcription, and proliferation, while also engaging a scaffold role to target ERK toward RSK2; it inhibits extrinsic apoptosis by binding FADD and caspase-8 at the DISC, blocking their activation; and it regulates glucose metabolism by interacting with PLD1 to activate PKC-α, which inhibits PKC-ζ and impairs insulin-stimulated GLUT4 recruitment. Its activities are tightly controlled by phosphorylation: PKC phosphorylates Ser104 (blocking ERK binding), and CaMKII, Akt, or AMPK phosphorylate Ser116 (promoting FADD binding, stabilizing the protein against ubiquitin-mediated degradation, and enabling anti-apoptotic function), whereas DUSP7 dephosphorylates PEA-15 to shift its output. Structural studies by NMR and crystallography have defined these interaction interfaces at atomic resolution.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEA-15 (PED/PEA-15) is a small cytoplasmic death effector domain (DED) adapter that acts as a phosphorylation-gated hub coordinating MAP kinase signaling, apoptosis, and glucose metabolism [#8, #20]. Through its DED and C-terminal tail it is a high-affinity bidentate ligand of ERK1/2, engaging the D-recruitment site together with the MAP kinase insert region to form a 1:1 complex; this anchors ERK in the cytoplasm via a nuclear export sequence, blocks ERK\\u2013nucleoporin interactions and nuclear entry, competes with D-site substrates such as Elk-1 and Ets-1, and protects bound ERK2 from dephosphorylation [#8, #15, #25, #30, #35]. Loss of PEA-15 raises nuclear phospho-ERK, cFos transcription and proliferation, and PEA-15 restrains tumor cell invasion and Ras-induced senescence escape through this ERK-tethering activity [#8, #18, #23]. PEA-15 also scaffolds ERK onto RSK2 to control CREB-dependent transcription [#14, #24]. In parallel, the DED binds FADD and caspase-8, displacing their interaction at the death-inducing signaling complex to block extrinsic (TNF\\u03b1, FasL, TRAIL) apoptosis, a function confirmed by increased death of PEA-15-null astrocytes [#4, #5, #17]. In metabolism, PEA-15 binds the C-terminal D4 domain of PLD1, driving constitutive PKC-\\u03b1 activation that inhibits insulin-responsive PKC-\\u03b6 and impairs GLUT4 recruitment and glucose uptake; transgenic overexpression causes diabetes by impairing both insulin action and glucose-stimulated insulin secretion [#2, #9, #28, #19, #26]. These outputs are switched by phosphorylation: PKC phosphorylates Ser104 to block ERK binding, while CaMKII, Akt, or AMPK phosphorylate Ser116 to promote FADD binding, anti-apoptotic function, and stabilization against ubiquitin- and chaperone-mediated degradation, and DUSP7 dephosphorylation reverses this switch [#0, #1, #13, #20, #36, #37, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established PEA-15 as a defined PKC phosphoprotein, providing the first regulatory handle before any function was known.\",\n      \"evidence\": \"In vitro kinase assay with purified PKC, 2D phosphopeptide mapping in astrocytes\",\n      \"pmids\": [\"8449955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PKC phosphorylation not yet defined\", \"Site not yet mapped to Ser104\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified a second, CaMKII-targeted site (Ser116) distinct from the PKC site, revealing dual-site control of PEA-15.\",\n      \"evidence\": \"Phosphopeptide microsequencing from endothelin-treated astrocytes plus in vitro CaMKII assay\",\n      \"pmids\": [\"9721757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effect of each site on partner binding not yet established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Connected PEA-15 to glucose metabolism, showing it inhibits insulin-stimulated glucose transport upstream of PKC.\",\n      \"evidence\": \"Stable overexpression in L6 muscle cells, glucose transport/GLUT4 assays with PKC inhibitor rescue\",\n      \"pmids\": [\"9670003\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PEA-15 binding partner mediating PKC activation not yet identified\", \"In vivo relevance not yet tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the anti-apoptotic mechanism: PEA-15 DED binds FADD and caspase-8 to disrupt DISC assembly, and genetic loss sensitizes cells to death.\",\n      \"evidence\": \"Reciprocal co-IP in MCF-7/HeLa, PARP cleavage assays, and PEA-15-null astrocyte survival assays\",\n      \"pmids\": [\"10442631\", \"10493725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation dependence of FADD binding not yet resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the canonical ERK-sequestration function: PEA-15 anchors ERK1/2 in the cytoplasm via a nuclear export sequence to restrain transcription and proliferation.\",\n      \"evidence\": \"PEA-15 knockout cells, NES mutant, ERK localization imaging, cFos reporter and proliferation assays\",\n      \"pmids\": [\"11702783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of ERK binding interface not yet defined\", \"Mechanism of nuclear-entry blockade unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Solved the PEA-15 structure and mapped ERK-binding residues, revealing a DED docking mode shared with death domains.\",\n      \"evidence\": \"NMR structure determination, chemical-shift footprinting, ERK-binding mutagenesis\",\n      \"pmids\": [\"12456656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic detail of the bound ERK2 complex not yet available\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified Akt as a direct Ser116 kinase that stabilizes PEA-15 against proteasomal degradation, coupling survival signaling to protein abundance.\",\n      \"evidence\": \"In vitro Akt kinase assay, S116G mutant, pulse-chase stability, phospho-specific antibody\",\n      \"pmids\": [\"12808093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the nuclear-entry blockade mechanism: PEA-15 and nucleoporins compete for the ERK2 MAP kinase insert region.\",\n      \"evidence\": \"Permeabilized-cell nuclear import assay with ERK2 insert mutants and nucleoporin binding assays\",\n      \"pmids\": [\"14707138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this fully accounts for cytoplasmic retention versus NES-mediated export not delineated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Quantified PEA-15 as a high-affinity bidentate ERK ligand at the D-recruitment site that competes with D-site substrates, explaining transcriptional inhibition.\",\n      \"evidence\": \"Fluorescence anisotropy binding, alkylation protection, in vitro kinase competition with Elk-1/Ets-1\",\n      \"pmids\": [\"17658892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the bidentate mode not yet visualized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reframed PEA-15 as a positive ERK scaffold that targets ERK to RSK2, showing it both sequesters and routes ERK.\",\n      \"evidence\": \"Co-IP, in vitro binding, RSK2 kinase and CREB reporter assays, PEA-15-null lymphocyte rescue\",\n      \"pmids\": [\"18077417\", \"12796492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation toggles between sequestration and scaffolding not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the metabolic mechanism in vivo and at the binding level: PED/PEA-15 binds the PLD1 D4 domain to drive PKC-\\u03b1\\u2013dependent PKC-\\u03b6 inhibition, causing diabetes.\",\n      \"evidence\": \"SPR binding, peptide competition rescue, PED transgenic and null mice, islet GSIS and PKC isoform assays\",\n      \"pmids\": [\"18541525\", \"15143191\", \"17327429\", \"11375323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Detailed signaling between PLD1 binding and PKC-\\u03b1 activation not fully mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Articulated the phosphorylation switch: Ser104 phosphorylation blocks ERK binding while Ser116 promotes FADD binding, partitioning PEA-15 between proliferation and apoptosis without changing its cytoplasmic distribution.\",\n      \"evidence\": \"Phosphomimetic/non-phosphorylatable mutants, in vitro binding, co-IP, fractionation, ERK reporter and integrin assays\",\n      \"pmids\": [\"15916534\", \"15917297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal coordination of the two kinases in vivo not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided atomic-resolution insight into ERK regulation: PEA-15 occupies both the D-recruitment and DEF-binding sites, allosterically disrupting active ERK2 and shielding it from dephosphorylation.\",\n      \"evidence\": \"X-ray crystallography of PEA-15/ERK2 in three phospho-conformations; stoichiometry by light scattering/AUC\",\n      \"pmids\": [\"23575685\", \"21506533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How allosteric inhibition reconciles with protection from dephosphorylation mechanistically not fully explained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended kinase control to AMPK and revealed chaperone-mediated autophagy as a second degradation route gated by phosphorylation.\",\n      \"evidence\": \"In vitro AMPK kinase assay and S116A mutant in mammospheres; TAP/HSC70 CMA substrate and KFERQ-motif mutagenesis\",\n      \"pmids\": [\"25096718\", \"24477641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of proteasomal versus CMA turnover in vivo not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified DUSP7 as the phosphatase reversing the PEA-15 switch, linking it to drug-resistance signaling downstream of FOSL1.\",\n      \"evidence\": \"ChIP, siRNA epistasis, phospho-PEA15 Western blot, doxorubicin resistance assays\",\n      \"pmids\": [\"34907034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; site specificity of DUSP7 dephosphorylation not mapped\", \"Direct phosphatase\\u2013substrate contact not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing PEA-15 outputs (ERK sequestration vs. RSK2/PLD1 scaffolding vs. DISC inhibition) are spatially and temporally integrated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how a single low-abundance adapter partitions among mutually exclusive partner pools\", \"Endogenous stoichiometry of PEA-15 versus ERK, FADD and PLD1 not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 20, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 14, 25, 35]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 15, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 25, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 5, 17]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 9, 19, 26]}\n    ],\n    \"complexes\": [\"death-inducing signaling complex (DISC)\"],\n    \"partners\": [\"MAPK1\", \"FADD\", \"CASP8\", \"PLD1\", \"RPS6KA3\", \"AKT1\", \"PRKAA1\", \"DUSP7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}