id: Q15121 gene_symbol: PEA15 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: PEA15 (PEA-15/PED) is a small (130 aa), ubiquitously expressed cytoplasmic phosphoprotein consisting of an N-terminal death effector domain (DED) and an unstructured C-terminal tail. It binds ERK1/2 (MAPK3/MAPK1) through a bipartite interaction in which the DED occupies the ERK DEF-docking site and the C-terminal tail occupies the D-recruitment site; bound ERK is held in the cytoplasm, its activation loop is distorted into an inactive conformation, and its dually phosphorylated state is protected from phosphatases, so that PEA15 acts as a cytoplasmic anchor and phosphorylation-gated reservoir for active ERK. Phosphorylation of PEA15 at Ser104 (PKC) and Ser116 (CaMKII/AKT) releases ERK. Through its DED, PEA15 also associates with FADD and caspase-8 and inhibits Fas- and TNFR1-induced caspase-8 activation and apoptosis. Overexpression in muscle and adipose cells impairs insulin-stimulated GLUT4 recruitment and glucose uptake. alternative_products: - name: '1' id: Q15121-1 - name: '2' id: Q15121-2 sequence_note: VSP_056174 existing_annotations: - term: id: GO:0000165 label: MAPK cascade evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR029546 review: summary: PEA15 regulates ERK1/2 signalling rather than acting as a cascade component. action: MODIFY reason: PEA15 is not a kinase or relay component of the MAPK cascade; it binds ERK1/2 and modulates their localization, conformation and dephosphorylation, inhibiting nuclear ERK signalling while preserving a pool of phospho-ERK that is released on PEA15 phosphorylation. The effect can be positive or negative depending on context, so the accurate process is regulation of the ERK1 and ERK2 cascade. proposed_replacement_terms: - id: GO:0070372 label: regulation of ERK1 and ERK2 cascade supported_by: - reference_id: PMID:23575685 supporting_text: "PEA-15 binding protects ERK2 from dephosphorylation, thus \nsetting the stage\ \ for immediate ERK activity upon its release from the PEA-15 \ninhibitory complex." - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:10442631 qualifier: enables supporting_entities: - UniProtKB:Q13158 review: summary: PEA15 co-precipitates with FADD; the interaction is DED-mediated. action: MODIFY reason: Bare protein binding is uninformative. In MCF-7 and HeLa lysates PEA15 co-precipitated with FADD, and the authors attribute displacement of FADD-caspase-8 binding to the PEA15 death effector domain; FADD binds partners through its own DED. Death effector domain binding captures the informative content of this interaction. proposed_replacement_terms: - id: GO:0035877 label: death effector domain binding supported_by: - reference_id: PMID:10442631 supporting_text: 'At least in part, this function may involve displacement of FADD-FLICE binding through the death effector domain of PED/PEA-15.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:10442631 qualifier: enables supporting_entities: - UniProtKB:Q14790 review: summary: PEA15 co-precipitates with caspase-8 (FLICE). action: MODIFY reason: Bare protein binding is uninformative. PEA15 co-precipitated with caspase-8 (FLICE) and reduced FADD-caspase-8 association and caspase-8 activation in response to TNF-alpha. Caspase binding is the informative replacement; a direct caspase inhibitor activity is not established because the effect is attributed to displacement from FADD rather than to inhibition of the protease. proposed_replacement_terms: - id: GO:0089720 label: caspase binding supported_by: - reference_id: PMID:10442631 supporting_text: PED/PEA-15 co-precipitated with both FADD and FLICE. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17255949 qualifier: enables supporting_entities: - UniProtKB:P28482 review: summary: PEA15 binds MAPK1 (ERK2). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding supported_by: - reference_id: PMID:17255949 supporting_text: Mxi2 acts antagonistically to PEA15, displacing it from ERK1/2 complexes - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21044950 qualifier: enables supporting_entities: - UniProtKB:Q9NYB0 review: summary: TERF2IP interaction from a genome-wide BiFC screen for telomere signalling regulators. action: REMOVE reason: Bare protein binding is uninformative. The TERF2IP (RAP1) interaction derives from a genome-wide YFP fluorescence-complementation screen and has no follow-up establishing a PEA15 function at telomeres or in NF-kappaB signalling; no more informative MF term is supported. Removal does not imply the reported interaction is false. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21900206 qualifier: enables supporting_entities: - UniProtKB:P27361 review: summary: PEA15 binds MAPK3 (ERK1). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23575685 qualifier: enables supporting_entities: - UniProtKB:P28482 review: summary: Crystal structures of PEA15 bound to three ERK2 phospho-conformers. action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. This structural study is the strongest evidence for the interaction, and also supports protein kinase regulator activity (core function). proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding supported_by: - reference_id: PMID:23575685 supporting_text: "PEA-15 uses a bipartite binding \nmode, occupying two key docking sites of ERK2" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables supporting_entities: - UniProtKB:P27361 review: summary: PEA15 binds MAPK3 (ERK1). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables supporting_entities: - UniProtKB:P28482 review: summary: PEA15 binds MAPK1 (ERK2). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables supporting_entities: - UniProtKB:P27361 review: summary: PEA15 binds MAPK3 (ERK1). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK3 (ERK1) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables supporting_entities: - UniProtKB:P28482 review: summary: PEA15 binds MAPK1 (ERK2). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables supporting_entities: - UniProtKB:P28482 review: summary: PEA15 binds MAPK1 (ERK2). action: MODIFY reason: Bare protein binding is uninformative. The cited study reports a PEA15-MAPK1 (ERK2) interaction; ERK1/2 are mitogen-activated protein kinases and PEA15's binding to them is the mechanistic basis of its ERK-regulatory function, so the informative term is mitogen-activated protein kinase binding. The interaction was detected in a proteome-scale screen and is consistent with the extensively characterised direct PEA15-ERK1/2 binding. proposed_replacement_terms: - id: GO:0051019 label: mitogen-activated protein kinase binding - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0086 review: summary: PEA15 is a cytoplasmic protein. action: ACCEPT reason: UniProt and the ERK-anchoring mechanism place PEA15 in the cytoplasm, where it retains ERK1/2 and prevents their nuclear translocation. supported_by: - reference_id: file:human/PEA15/PEA15-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: PEA15 is a soluble cytosolic ERK anchor. action: ACCEPT reason: Immunofluorescence (HPA) and the Reactome curation both place PEA15 in the cytosol, consistent with a soluble DED protein lacking membrane-targeting features that sequesters ERK1/2 outside the nucleus. supported_by: - reference_id: Reactome:R-HSA-5675206 supporting_text: PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5675206 qualifier: located_in review: summary: PEA15 is a soluble cytosolic ERK anchor. action: ACCEPT reason: Immunofluorescence (HPA) and the Reactome curation both place PEA15 in the cytosol, consistent with a soluble DED protein lacking membrane-targeting features that sequesters ERK1/2 outside the nucleus. supported_by: - reference_id: Reactome:R-HSA-5675206 supporting_text: PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus - term: id: GO:0005875 label: microtubule associated complex evidence_type: NAS original_reference_id: PMID:8662970 qualifier: part_of review: summary: Association of PEA15 with microtubules was reported in mouse astrocytes; there is no evidence for a defined complex. action: MODIFY reason: The cited abstract describes PEA-15 as a protein kinase C substrate associated with microtubules, citing earlier mouse astrocyte work; UniProt records the same association. GO:0005875 denotes a multimeric complex connected to microtubules, and no such complex containing PEA15 has been defined. Location on the microtubule cytoskeleton is the claim actually made. This is a non-core, NAS-level observation from the mouse ortholog (same PANTHER subfamily PTHR48169:SF1, 96% identical). proposed_replacement_terms: - id: GO:0015630 label: microtubule cytoskeleton supported_by: - reference_id: PMID:8662970 supporting_text: 'PEA-15, a protein kinase C substrate associated with microtubules' - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in supporting_entities: - InterPro:IPR001875 - InterPro:IPR029546 review: summary: Correct but general; PEA15 inhibits death-receptor-induced apoptosis specifically. action: MODIFY reason: The InterPro DED mapping is correct in direction but general. The experimental evidence is specifically for inhibition of Fas- and TNFR1-induced apoptosis by interference with FADD-caspase-8 association, which the gene already carries as GO:1902042 (IDA and IBA). proposed_replacement_terms: - id: GO:1902042 label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors supported_by: - reference_id: PMID:10442631 supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis.' - term: id: GO:0046325 label: negative regulation of D-glucose import across plasma membrane evidence_type: IDA original_reference_id: PMID:9670003 qualifier: involved_in review: summary: PEA15 overexpression inhibits insulin-stimulated glucose transport in L6 myotubes. action: KEEP_AS_NON_CORE reason: Overexpression of human PEA15 in L6 skeletal muscle cells inhibited insulin-stimulated glucose transport and GLUT4 recruitment to the surface; the term matches this regulatory observation. It is a gain-of-function phenotype linked to the type 2 diabetes overexpression finding, mediated indirectly (via PLD1/PKC signalling), and peripheral to the core ERK-anchoring and DED functions. PEA15 has no transporter activity. supported_by: - reference_id: PMID:9670003 supporting_text: 'Transfection of PED/PEA-15 in differentiating L6 skeletal muscle cells increases the content of Glut1 transporters on the plasma membrane and inhibits insulin-stimulated glucose transport and cell-surface recruitment of Glut4' - term: id: GO:1902042 label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:104799 - PANTHER:PTN008298780 - UniProtKB:Q15121 review: summary: PEA15 inhibits Fas- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. action: ACCEPT reason: The PAINT node PTN008298780 sits within the PEA15 orthologue clade (PANTHER PTHR48169:SF1) and is grounded in human (this gene, IDA) and mouse Pea15 experimental data; the human protein is a direct descendant, so the inference is sound. The DED-mediated anti-apoptotic function is a defining activity of the PEA15 branch, distinct from the CFLAR (SF3) and caspase-8/10 (SF7) subfamilies. supported_by: - reference_id: PMID:10442631 supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis.' - term: id: GO:1902042 label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors evidence_type: IDA original_reference_id: PMID:10442631 qualifier: involved_in review: summary: PEA15 inhibits Fas- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. action: ACCEPT reason: 'Primary human-cell experiment: overexpressed PEA15 blocked FasL and TNF-alpha apoptosis, co-precipitated with FADD and caspase-8, reduced FADD-caspase-8 co-precipitation and caspase-8 activation. PEA15 itself performs the inhibitory step, so this is genuine regulatory participation.' supported_by: - reference_id: PMID:10442631 supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis.' - term: id: GO:1902042 label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in supporting_entities: - ARBA:ARBA00088654 review: summary: PEA15 inhibits Fas- and TNFR1-induced apoptosis by interfering with FADD-caspase-8 association via its DED. action: ACCEPT reason: Consistent with the experimental IDA and IBA rows for the same term; the ARBA prediction adds nothing independent but asserts a correct claim. supported_by: - reference_id: PMID:10442631 supporting_text: 'Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis.' - term: id: GO:0042308 label: negative regulation of protein import into nucleus evidence_type: IDA original_reference_id: PMID:23575685 review: summary: PEA15 retains ERK1/2 in the cytoplasm and blocks their nuclear translocation. action: NEW reason: 'PEA15 is the entity that performs this step: by occupying the ERK DEF and D docking sites it masks the surfaces ERK uses to engage nuclear transport machinery. In the structure paper, the PEA15 L123K docking mutant fails to prevent ERK nuclear translocation, and the R71 interface mutant abrogates cytoplasmic retention; Reactome and the Mxi2 study describe the same cytoplasmic-anchor function. This is the direct mechanism rather than a downstream phenotype.' supported_by: - reference_id: PMID:23575685 supporting_text: results in the failure of the PEA-15 L123K mutant to prevent ERK nuclear translocation - reference_id: Reactome:R-HSA-5675206 supporting_text: PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus - term: id: GO:0019887 label: protein kinase regulator activity evidence_type: IDA original_reference_id: PMID:23575685 review: summary: PEA15 directly modulates ERK2 conformation and phosphorylation state. action: NEW reason: Crystal structures show that PEA15 binding triggers an allosteric conduit that disrupts key features of active ERK2, holding the activation loop in an inactive conformation, while also protecting the bound kinase from dephosphorylation; interface mutants lose these effects in cells. PEA15 acts directly on the kinase, so a kinase regulator activity is appropriate. A strict inhibitor term is avoided because the net cellular outcome depends on PEA15 phosphorylation and can favour cytoplasmic ERK output. supported_by: - reference_id: PMID:23575685 supporting_text: "PEA-15 binding triggers an extended allosteric \nconduit in dually phosphorylated\ \ ERK2, disrupting key features of active ERK2." references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:10442631 title: 'PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary human-cell study of DED-mediated inhibition of Fas/TNFR1 apoptosis and FADD/caspase-8 co-precipitation; abstract-only cache. - id: PMID:17255949 title: Mxi2 promotes stimulus-independent ERK nuclear translocation. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mxi2 study; PEA15 shown to compete with Mxi2 for ERK1/2 binding. - id: PMID:21044950 title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Genome-wide BiFC screen; source of the TERF2IP interaction only. - id: PMID:21900206 title: A directed protein interaction network for investigating intracellular signal transduction. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Directed protein interaction network screen; ERK1 interaction. - id: PMID:23575685 title: Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Crystal structures of ERK2-PEA15 complexes plus cell assays (nuclear translocation, dephosphorylation protection); full text cached. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: HuRI binary interactome; ERK1/2 interactions. - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: BioPlex dual proteome-scale network; ERK1/2 interactions. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Multimodal cell map; ERK2 interaction. - id: PMID:8662970 title: The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Mouse/human PEA-15 cDNA cloning; abstract mentions microtubule association from earlier mouse astrocyte work. - id: PMID:9670003 title: PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Human PEA15 overexpression in L6 cells inhibits insulin-stimulated glucose uptake; overexpressed in type 2 diabetes. Abstract-only cache. - id: Reactome:R-HSA-5675206 title: PEA15 binds MAPK monomers and dimers findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Reactome reaction summarising PEA15 as cytoplasmic anchor for activated MAPKs. - id: file:human/PEA15/PEA15-uniprot.txt title: 'UniProtKB Q15121: human PEA15 curated sequence and functions' findings: [] core_functions: - description: 'Cytoplasmic anchoring and conformational regulation of ERK1/2: PEA15 binds ERK1/2 via its DED (DEF site) and C-terminal tail (D site), restraining kinase activity and nuclear entry while protecting the phosphorylated activation loop from phosphatases; phosphorylation of PEA15 releases active ERK.' molecular_function: id: GO:0019887 label: protein kinase regulator activity directly_involved_in: - id: GO:0070372 label: regulation of ERK1 and ERK2 cascade - id: GO:0042308 label: negative regulation of protein import into nucleus locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:23575685 supporting_text: "PEA-15 uses a bipartite binding \nmode, occupying two key docking sites of ERK2" - reference_id: PMID:23575685 supporting_text: PEA-15 binding protects ERK2 from dephosphorylation - description: 'DED-mediated inhibition of death-receptor apoptosis: PEA15 associates with FADD and caspase-8 and interferes with their association at the death-inducing signalling complex, lowering caspase-8 activation after Fas or TNFR1 stimulation.' molecular_function: id: GO:0035877 label: death effector domain binding directly_involved_in: - id: GO:1902042 label: negative regulation of extrinsic apoptotic signaling pathway via death domain receptors locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:10442631 supporting_text: 'PED/PEA-15-FLICE association was inhibited by overexpression of the wild-type but not of a DED-deletion mutant of FADD.' suggested_questions: - question: Should PEA15 receive a protein sequestering activity (GO:0140311) annotation for ERK1/2 and RSK2, or is protein kinase regulator activity the preferred MF for a cytoplasmic kinase anchor that also protects its target from dephosphorylation? - question: Does the DED of PEA15 bind FADD directly in purified form, or is co-precipitation with FADD and caspase-8 bridged by other DISC components? suggested_experiments: - description: Reconstitute FADD-caspase-8 DED filament assembly in vitro with purified PEA15 (wild type, DED mutants, S104/S116 phosphomimetics) to test whether PEA15 caps or displaces filaments directly.