{"gene":"PEBP1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1999,"finding":"RKIP (PEBP1) binds to Raf-1 and MEK in vitro and co-immunoprecipitates with Raf-1 and MEK from cell lysates, competitively disrupting the Raf-1/MEK interaction and thereby inhibiting MEK phosphorylation and ERK activation. RKIP is not a substrate for Raf-1 or MEK. Overexpression inhibits MEK/ERK/AP-1 activation; antisense or antibody microinjection activates MEK/ERK/AP-1.","method":"Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, confocal colocalization, reporter gene assay, antisense RNA/antibody microinjection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro binding, functional overexpression and loss-of-function), foundational paper replicated extensively","pmids":["10490027"],"is_preprint":false},{"year":2004,"finding":"PKC phosphorylates RKIP, causing release of Raf-1 and activation of MEK/ERK. The phosphorylated form of RKIP then binds to and inhibits G-protein-coupled receptor kinase 2 (GRK2), resulting in sustained G-protein signaling — establishing RKIP as a molecular switch between two distinct kinase-inhibitory states.","method":"Biochemical/pharmacological assays described in review citing primary experimental work","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic model supported by primary experimental data cited across multiple labs; abstracted here as a review summary, limiting direct method verification","pmids":["15313400"],"is_preprint":false},{"year":2005,"finding":"RKIP interacts with B-Raf (in addition to Raf-1) and antagonizes its kinase activity. Yeast two-hybrid and co-immunoprecipitation confirmed RKIP–B-Raf interaction; ectopic RKIP expression reduced B-Raf kinase activity independently of its known inhibitory action on Raf-1.","method":"Yeast two-hybrid, co-immunoprecipitation, kinase activity assay, ectopic overexpression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Y2H and Co-IP plus functional kinase assay in same study","pmids":["15782137"],"is_preprint":false},{"year":2017,"finding":"PEBP1 forms a complex with 15-lipoxygenase isoforms 15LO1 and 15LO2, altering their substrate specificity from free polyunsaturated fatty acids to phosphatidylethanolamine (PE), enabling generation of hydroperoxy-PE (HpETE-PE) — the proximate ferroptotic death signal. This PEBP1/15LO complex is required for ferroptotic cell death in airway epithelial cells, kidney epithelial cells, and neurons.","method":"Co-immunoprecipitation, lipidomic analysis (redox lipidomics), cell-based ferroptosis models (airway, renal, neuronal), genetic loss-of-function","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP of complex, substrate specificity assay, multiple independent cell/tissue models, replicated by subsequent studies","pmids":["29053969"],"is_preprint":false},{"year":2011,"finding":"RKIP binds GSK3 proteins and maintains GSK3β protein levels and active form. RKIP depletion activates p38 MAPK which phosphorylates GSK3β at inhibitory T390, de-repressing GSK3β substrates cyclin D, β-catenin, SNAIL and SLUG, promoting cell-cycle progression and EMT.","method":"Co-immunoprecipitation, RKIP knockdown/overexpression, phosphorylation assays, Western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing RKIP–GSK3 binding plus functional knockdown with defined phosphorylation readouts, single lab","pmids":["21303975"],"is_preprint":false},{"year":2011,"finding":"RKIP inhibits breast tumor metastasis in part through a pathway involving let-7 miRNA, which suppresses let-7 targets HMGA2 and BACH1; BACH1 is a transcription factor that induces MMP1 expression and promotes bone metastasis genes (MMP1, OPN, CXCR4).","method":"Statistical analysis of tumor gene expression combined with experimental validation (overexpression, knockdown, reporter assays)","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — experimental validation of pathway with multiple gene knockdowns and expression analysis, single lab","pmids":["21873975"],"is_preprint":false},{"year":2014,"finding":"CDK5 phosphorylates RKIP at T42 in neurons, causing release of Raf-1. T42 phosphorylation also exposes the C-terminal motif 'KLYEQ', recognized by chaperone Hsc70, leading to chaperone-mediated autophagy (CMA) degradation of RKIP. This CDK5/RKIP/ERK pathway is activated in Parkinson's disease models, leading to ERK overactivation, S-phase re-entry, and neuronal loss.","method":"In vitro kinase assay (CDK5 phosphorylation), mutagenesis (T42), co-immunoprecipitation (Hsc70/RKIP), CMA degradation assay, PD mouse models and patient brain samples","journal":"Neurobiology of aging","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis, CMA degradation assay, validated in disease models; single lab but multiple orthogonal methods","pmids":["25104559"],"is_preprint":false},{"year":2016,"finding":"PEBP1 contains a functional LC3-interacting region (LIR) motif (WXXL) that mediates direct binding to PE-unconjugated LC3. PEBP1 overexpression inhibits starvation-induced autophagy by activating AKT–mTORC1 signaling and suppressing ULK1 activity. Mutation of the LIR motif (AXXA) disrupts LC3 binding but promotes rather than inhibits autophagy. Phosphorylation of PEBP1 at Ser153 dissociates the PEBP1–LC3 complex to allow autophagy induction.","method":"Co-immunoprecipitation, LIR motif mutagenesis, autophagy flux assays, AKT/mTORC1/ULK1 phosphorylation analysis, overexpression/knockdown","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding shown by Co-IP, functional mutagenesis of LIR motif, multiple pathway readouts, single lab","pmids":["27540684"],"is_preprint":false},{"year":2020,"finding":"PEBP1 interacts with both 15LO1 (proferroptotic) and the autophagic protein LC3, acting as a rheostat. The 15LO1-PEBP1-generated ferroptotic lipid 15-HpETE-PE promotes LC3-I lipidation to stimulate compensatory autophagy, protecting cells from ferroptotic death.","method":"Co-immunoprecipitation, lipidomic analysis, autophagy flux assays, human airway epithelial cell models, asthma patient samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of PEBP1 with both 15LO1 and LC3, functional lipidomic and autophagy readouts, validated in patient samples; single lab but multiple orthogonal methods","pmids":["32513718"],"is_preprint":false},{"year":2020,"finding":"Ferrostatin-1 (Fer-1) does not inhibit 15LOX alone, but effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows Fer-1 binds to the 15LOX/PEBP1 complex at three sites, disrupting allosteric motions required for catalysis.","method":"Biochemical inhibition assay (15LOX alone vs. complex), computational molecular docking/modeling, redox lipidomics in nine ferroptosis cell/tissue models","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic activity assay distinguishing 15LOX alone from 15LOX/PEBP1 complex, computational binding analysis, replicated across nine models","pmids":["33126055"],"is_preprint":false},{"year":2020,"finding":"PEBP1 suppresses HIV-1 transcription and induces latency by de-phosphorylating Raf1/ERK/IκB and IKK/IκB signaling pathways, sequestering NF-κB in the cytoplasm and preventing transcriptional activation of HIV-1. Identified via genome-wide CRISPR-Cas9 knockout screen.","method":"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation assays, NF-κB nuclear translocation assays, HIV latency models (multiple cell lines + primary CD4+ T cells from ART patients)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased CRISPR screen plus mechanistic validation (phosphorylation assays, NF-κB localization) replicated in multiple latency models","pmids":["32924251"],"is_preprint":false},{"year":2020,"finding":"RKIP directly binds ASC (apoptosis-associated speck-like protein containing a CARD domain) and competes with NLRP1, NLRP3, and NLRC4 for ASC interaction, thereby interrupting inflammasome assembly and activation and suppressing caspase-1 activation and IL-1β secretion.","method":"Co-immunoprecipitation, overexpression/knockdown in THP-1 cells and primary macrophages, RKIP-deficient mouse models (Alum-induced peritonitis, Salmonella infection)","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding (Co-IP), competition assay, loss-of-function in primary cells and in vivo models with defined inflammasome readouts","pmids":["32901127"],"is_preprint":false},{"year":2018,"finding":"RKIP directly interacts with IL-17RA and Act1 to promote formation of an IL-17R–Act1 complex, resulting in enhanced MAPK and NF-κB activation and downstream pro-inflammatory cytokine production. RKIP-deficient mice show ameliorated experimental autoimmune encephalomyelitis (EAE) specifically through the Th17-mediated pathway.","method":"Co-immunoprecipitation (RKIP with IL-17RA and Act1), RKIP-knockout mouse EAE model, adoptive T-cell transfer, cytokine production assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of ternary complex, RKIP-KO mouse with defined phenotype, adoptive transfer epistasis experiment","pmids":["29674348"],"is_preprint":false},{"year":2022,"finding":"PEBP1 complexes with RIP3 kinase and inhibits necroptosis. When 15LOX is expressed at elevated levels (higher affinity for PEBP1), it competes with RIP3 to sequester PEBP1, switching cell death from necroptosis to ferroptosis. RIP3 K51A kinase-inactive mice show increased ferroptotic burden rescued by anti-ferroptotic compounds.","method":"Co-immunoprecipitation (PEBP1–RIP3), genetic models (Rip3K51A/K51A mice), redox lipidomics, biochemical competition assays, computational structural analysis","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP of novel PEBP1–RIP3 complex, in vivo genetic model with rescue by antiferroptotic drugs, multiple orthogonal methods","pmids":["35101798"],"is_preprint":false},{"year":2022,"finding":"CircPOLR2A interacts with both UBE3C and PEBP1 to form a ternary RNA-protein complex. UBE3C acts as a specific E3 ubiquitin ligase for PEBP1, and circPOLR2A enhances UBE3C-mediated ubiquitination and proteasomal degradation of PEBP1, thereby activating ERK signaling in clear cell renal cell carcinoma.","method":"RNA pull-down, mass spectrometry, RIP assay, Co-IP, Western blot (ubiquitination), rescue experiments","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down and Co-IP demonstrate ternary complex; ubiquitination assay shows UBE3C as E3 ligase for PEBP1; single lab","pmids":["35840930"],"is_preprint":false},{"year":2018,"finding":"RIPK4 promotes proteasome-mediated degradation of PEBP1, thereby activating RAF1/MEK/ERK signaling. Suppression of PEBP1 degradation eliminates RIPK4-induced ERK activation and pancreatic cancer cell migration/invasion.","method":"High-throughput screening, Western blot (proteasome-mediated PEBP1 degradation), PEBP1 rescue experiments, migration/invasion assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments establishing causal link between RIPK4, PEBP1 degradation, and ERK pathway; single lab","pmids":["29436617"],"is_preprint":false},{"year":2009,"finding":"Human and bovine PEBP1 directly interact with morphine glucuronides (M3G and M6G) but not with morphine itself. M6G binds PEBP1 in a manner similar to the reference ligand phosphatidylethanolamine (PE), and PEBP1 displays similar affinity for PE, M6G, and M3G.","method":"Noncovalent electrospray ionization mass spectrometry (ESI-MS) of protein–ligand complexes","journal":"Medical science monitor","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical method (noncovalent MS) establishing direct binding, single lab single study","pmids":["19564817"],"is_preprint":false},{"year":2010,"finding":"NMR screening identified that the conserved ligand-binding pocket of RKIP binds phospholipid DHPE and three novel small-molecule ligands. Occupation of this pocket by DHPE regulates RKIP interaction with Raf-1; phosphorylation of RKIP at Ser-153 also regulates Raf-1 binding. The newly identified ligands did not affect RKIP–Raf-1 binding or RKIP phosphorylation.","method":"High-resolution heteronuclear NMR spectroscopy (chemical shift perturbation), compound library screening","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR-based binding characterization under near-physiological conditions; single lab","pmids":["20463977"],"is_preprint":false},{"year":2012,"finding":"NMR mapping of human PEBP1 binding sites for GTP, FMN, and Raf-1 peptides (phosphorylated and non-phosphorylated) shows all ligands bind to the same region centered on the conserved ligand-binding pocket. Residues in the vicinity of, rather than within, the pocket appear required for Raf-1 interaction.","method":"NMR (chemical shift perturbation mapping), native mass spectrometry (KD measurement)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR plus MS for ligand binding characterization; single lab","pmids":["22558375"],"is_preprint":false},{"year":2006,"finding":"PEBP1 is a substrate of calpain protease in vitro and in situ (brain injury model). PEBP1 also inhibits the chymotrypsin-like activity of the 26S proteasome by approximately 30% in vitro.","method":"In vitro proteolysis assay, in situ brain injury model, proteasome activity assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay plus in situ confirmation; single lab, single study","pmids":["17018026"],"is_preprint":false},{"year":2023,"finding":"Computational simulations and lipidomic experiments show that membrane association of the 15LOX-1/PEBP1 complex triggers a conformational change facilitating access of stearoyl/arachidonoyl-PE (SAPE) substrate to the catalytic site. PEBP1 P112E mutation significantly impairs generation of the predominant ferroptotic product 15-HpETE-PE. The complex produces 15-HpETE-PE and 12-HpETE-PE at a 5:1 ratio.","method":"Computational molecular dynamics simulation, mutagenesis (P112E), LC-MS/MS lipidomics, membrane interaction assays","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with quantitative lipidomics and computational modeling in same study","pmids":["37678654"],"is_preprint":false},{"year":2023,"finding":"FerroLOXIN-1 and -2 inhibit ferroptosis by specifically interacting with the 15LOX-2/PEBP1 complex: one compound alters substrate (ETE-PE) binding pose nonproductively, the other blocks the predominant oxygen channel, preventing ETE-PE peroxidation. Effects are not due to radical scavenging or iron chelation.","method":"Biochemical assay (15LOX/PEBP1 complex vs. 15LOX alone), computational docking, redox lipidomics, cell biology models, in vivo testing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mechanistic inhibitor studies with complex-specific biochemical assays, computational mechanism determination, and in vivo validation","pmids":["37327313"],"is_preprint":false},{"year":2012,"finding":"MDA-9/syntenin transcriptionally downregulates RKIP, and MDA-9 physically interacts with RKIP in melanoma cells. This interaction correlates with suppression of FAK and c-Src phosphorylation, blocking MDA-9-mediated FAK/c-Src complex formation needed for metastatic signaling.","method":"Tumor array, co-immunoprecipitation (MDA-9–RKIP), phosphorylation assays (FAK/c-Src), ectopic RKIP expression, in vivo tumor dissemination assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of novel RKIP–MDA-9 complex, functional phosphorylation readouts, in vivo validation; single lab","pmids":["23066033"],"is_preprint":false},{"year":2021,"finding":"RKIP activates RhoA in an Erk2- and GEF-H1-dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression, thereby suppressing breast cancer cell invasion and metastasis.","method":"RhoA activity assay, co-immunoprecipitation, loss/gain-of-function (RKIP, GEF-H1), E-cadherin localization (imaging), CCL5 expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTPase activity assay, Co-IP, functional imaging and expression assays; single lab","pmids":["34465801"],"is_preprint":false},{"year":2021,"finding":"CELF1 (RNA-binding protein) directly binds to fragment 1 within the 3'UTR of PEBP1 mRNA (shown by RNA immunoprecipitation and biotin pull-down), post-transcriptionally suppressing PEBP1 protein expression without affecting PEBP1 mRNA levels. CELF1-mediated PEBP1 suppression activates MAPK signaling (Raf1, TAK1, ERK1/2, p38) and promotes cardiac hypertrophy.","method":"RNA immunoprecipitation (RIP), biotin RNA pull-down, dual-luciferase assay, CELF1 overexpression/depletion, TAC cardiac hypertrophy mouse model","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and biotin pull-down establish direct CELF1–PEBP1 mRNA interaction; functional cardiac model; single lab","pmids":["34669021"],"is_preprint":false},{"year":2015,"finding":"RKIP negatively regulates MMP13 expression through the Erk2 signaling pathway in a transcription factor AP-1-independent manner, thereby inhibiting local breast cancer cell invasion. Loss/gain-of-function experiments show MMP13 as the causal downstream effector of RKIP-mediated invasion suppression.","method":"PCR-based screening, DNA microarray analysis, loss/gain-of-function (RKIP, MMP13), invasion assays, Erk2 pathway analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combinatorial loss/gain-of-function establishes epistatic relationship; single lab","pmids":["26308852"],"is_preprint":false}],"current_model":"PEBP1/RKIP is a multifunctional scaffold inhibitor that (1) directly inhibits Raf-1 and B-Raf kinase activity by competitively blocking Raf–MEK interaction; (2) upon PKC phosphorylation at Ser153, switches to inhibit GRK2; (3) is phosphorylated by CDK5 at T42 triggering chaperone-mediated autophagy degradation; (4) forms a complex with 15-lipoxygenases (15LOX1/2) that redirects their substrate specificity toward phosphatidylethanolamines, generating pro-ferroptotic HpETE-PE death signals; (5) acts as a necroptosis-to-ferroptosis switch by competing with RIP3 for PEBP1 binding; (6) directly binds LC3 via an LIR motif to negatively regulate autophagy through AKT–mTORC1; (7) binds ASC to block NLRP1/3/NLRC4 inflammasome assembly; (8) interacts with IL-17RA/Act1 to promote IL-17R signaling; and (9) suppresses NF-κB-driven HIV transcription and can be degraded via UBE3C-mediated ubiquitination."},"narrative":{"mechanistic_narrative":"PEBP1 (RKIP) is a multifunctional small scaffold/regulatory protein that controls cell fate decisions by physically gating signaling kinases and lipid-oxidizing enzymes [PMID:10490027, PMID:29053969]. Its founding function is direct inhibition of the Raf/MEK/ERK cascade: it binds Raf-1 and MEK without being a substrate, competitively disrupting the Raf-1/MEK interaction to block MEK phosphorylation and ERK/AP-1 activation, and it similarly antagonizes B-Raf kinase activity [PMID:10490027, PMID:15782137]. This inhibitory grip is conditional — PKC phosphorylation releases Raf-1 and converts RKIP into a GRK2 inhibitor, establishing it as a phosphorylation-controlled molecular switch between two kinase-inhibitory states [PMID:15313400]. Through ERK suppression, PEBP1 restrains tumor invasion and metastasis, acting via GSK3β stabilization, a let-7/HMGA2/BACH1 axis, RhoA/GEF-H1-dependent E-cadherin localization, and repression of MMP13 [PMID:21303975, PMID:21873975, PMID:34465801, PMID:26308852]. A distinct moonlighting activity emerged from its association with 15-lipoxygenases (15LO1/15LO2): the PEBP1/15LOX complex redirects enzyme substrate specificity from free fatty acids to phosphatidylethanolamine, generating the pro-ferroptotic death signal 15-HpETE-PE, a reaction requiring membrane-triggered conformational change and tunable by point mutations (P112E) and complex-selective inhibitors [PMID:29053969, PMID:37678654, PMID:37327313]. PEBP1 thereby integrates death-pathway choices, competing with RIP3 to switch cells between necroptosis and ferroptosis and binding LC3 through an LIR motif to modulate autophagy via AKT–mTORC1 [PMID:35101798, PMID:27540684, PMID:32513718]. It further suppresses inflammation by sequestering ASC to block NLRP1/3/NLRC4 inflammasome assembly, promotes IL-17R–Act1 signaling, and enforces HIV-1 latency by dephosphorylating Raf1/ERK and IKK/IκB to sequester NF-κB [PMID:32901127, PMID:29674348, PMID:32924251]. PEBP1 protein levels are themselves controlled by phosphorylation-triggered chaperone-mediated autophagy (CDK5/T42), CELF1-mediated translational repression, and proteasomal degradation directed by UBE3C and RIPK4 [PMID:25104559, PMID:34669021, PMID:35840930, PMID:29436617].","teleology":[{"year":1999,"claim":"Established the founding mechanism: how an endogenous protein restrains the Raf/MEK/ERK cascade, by showing RKIP physically competes Raf-1 away from MEK.","evidence":"Yeast two-hybrid, in vitro binding, Co-IP, and antisense/antibody microinjection in cells","pmids":["10490027"],"confidence":"High","gaps":["Did not resolve the structural basis of Raf-1/MEK competition","Did not address regulation of RKIP itself"]},{"year":2004,"claim":"Answered how RKIP inhibitory specificity is toggled, defining a PKC-phosphorylation switch from Raf-1 inhibition to GRK2 inhibition.","evidence":"Biochemical/pharmacological assays summarized in a review citing primary work","pmids":["15313400"],"confidence":"Medium","gaps":["Abstracted from review, limiting direct method verification","Stoichiometry and kinetics of the switch not defined"]},{"year":2005,"claim":"Extended Raf inhibition to B-Raf, showing the inhibitory scope is broader than Raf-1 alone.","evidence":"Yeast two-hybrid, Co-IP, and kinase activity assay with ectopic expression","pmids":["15782137"],"confidence":"High","gaps":["Did not establish whether B-Raf and Raf-1 inhibition use identical interfaces"]},{"year":2006,"claim":"Identified PEBP1 as a calpain substrate and a partial proteasome inhibitor, first hints that its stability and protease interplay are regulated.","evidence":"In vitro proteolysis, in situ brain injury model, proteasome activity assay","pmids":["17018026"],"confidence":"Medium","gaps":["Physiological relevance of calpain cleavage uncharacterized","Mechanism of proteasome inhibition not defined"]},{"year":2011,"claim":"Connected RKIP loss to metastasis programs, defining downstream GSK3β-stabilizing and let-7/HMGA2/BACH1 axes that drive EMT and bone-metastasis genes.","evidence":"Co-IP, knockdown/overexpression with phosphorylation readouts, and tumor expression analysis with reporter validation","pmids":["21303975","21873975"],"confidence":"Medium","gaps":["Single-lab pathway models","Direct versus indirect regulation of miRNA axis not fully separated"]},{"year":2012,"claim":"Mapped the conserved ligand-binding pocket and additional partners (MDA-9/syntenin), clarifying that pocket occupancy and adjacent residues govern Raf-1 binding.","evidence":"NMR chemical shift mapping and native MS; Co-IP and phosphorylation/in vivo dissemination assays for MDA-9","pmids":["22558375","23066033"],"confidence":"Medium","gaps":["Functional consequence of GTP/FMN binding unresolved","No crystal structure of Raf-1-bound complex"]},{"year":2014,"claim":"Revealed how PEBP1 levels are controlled, defining CDK5 phosphorylation at T42 that releases Raf-1 and triggers Hsc70-dependent chaperone-mediated autophagy degradation in neurodegeneration.","evidence":"In vitro CDK5 kinase assay, T42 mutagenesis, CMA degradation assay, PD mouse and patient samples","pmids":["25104559"],"confidence":"High","gaps":["Single lab","Generality of CMA route beyond neurons not established"]},{"year":2016,"claim":"Defined a non-kinase function, showing a functional LIR motif binds LC3 and negatively regulates autophagy via AKT–mTORC1/ULK1, gated by Ser153 phosphorylation.","evidence":"Co-IP, LIR mutagenesis (AXXA), autophagy flux, and pathway phosphorylation analysis","pmids":["27540684"],"confidence":"High","gaps":["Single lab","How LC3 binding mechanistically alters AKT–mTORC1 not fully resolved"]},{"year":2017,"claim":"Established the ferroptosis mechanism, showing the PEBP1/15LOX complex reprograms enzyme specificity toward phosphatidylethanolamine to generate the proximate HpETE-PE death signal.","evidence":"Co-IP, redox lipidomics, and genetic loss-of-function across airway, renal, and neuronal ferroptosis models","pmids":["29053969"],"confidence":"High","gaps":["Structural basis of substrate redirection not yet resolved at this stage"]},{"year":2018,"claim":"Expanded PEBP1 into immune signaling and degradation control, showing it builds the IL-17RA–Act1 complex and is degraded by RIPK4 to license RAF1/MEK/ERK-driven cancer invasion.","evidence":"Co-IP of ternary complex with RKIP-KO EAE/adoptive transfer; high-throughput screen with PEBP1 rescue and invasion assays","pmids":["29674348","29436617"],"confidence":"High","gaps":["Mechanism of RIPK4-directed degradation (E3 ligase) not identified in this study","Direct versus scaffolded IL-17R assembly not structurally resolved"]},{"year":2020,"claim":"Positioned PEBP1 as an integrator of death and inflammation, linking ferroptosis to compensatory autophagy, blocking inflammasome assembly via ASC, and enforcing HIV-1 latency by sequestering NF-κB.","evidence":"Co-IP/lipidomics/autophagy flux (15LO1–PEBP1–LC3); ASC competition with inflammasome readouts in macrophages and KO mice; genome-wide CRISPR screen plus NF-κB localization in latency models; complex-specific Fer-1 inhibition with computational docking","pmids":["32513718","32901127","32924251","33126055"],"confidence":"High","gaps":["How a single protein partitions among 15LOX, LC3, ASC, and NF-κB pathways in one cell is unresolved","Inhibitor binding sites inferred computationally"]},{"year":2022,"claim":"Defined the death-mode switch and a degradation route, showing PEBP1 binds RIP3 to restrain necroptosis with 15LOX competing it toward ferroptosis, and that circPOLR2A/UBE3C ubiquitinates PEBP1.","evidence":"Co-IP, Rip3K51A mouse rescue, redox lipidomics, competition assays; RNA pull-down/MS/RIP and ubiquitination assays for UBE3C","pmids":["35101798","35840930"],"confidence":"High","gaps":["Affinity-based competition thresholds in vivo not quantified","circPOLR2A/UBE3C axis is single-lab"]},{"year":2023,"claim":"Resolved the catalytic mechanism of the ferroptotic complex, showing membrane association triggers a conformational change enabling PE substrate access, and developed complex-selective inhibitors.","evidence":"Molecular dynamics, P112E mutagenesis with LC-MS/MS lipidomics; FerroLOXIN inhibitor studies with docking and in vivo testing","pmids":["37678654","37327313"],"confidence":"High","gaps":["No experimental high-resolution structure of the membrane-bound complex","In vivo therapeutic window of inhibitors not defined"]},{"year":null,"claim":"How PEBP1 dynamically partitions its single ligand pocket and interaction surfaces among competing partners (Raf/MEK, GRK2, 15LOX, LC3, ASC, RIP3) within one cell, and what governs that allocation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative competition model across partners","No structure of PEBP1 in its alternative complexes","Cell-type determinants of which function dominates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,1,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,12,13]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[16,17,18]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,13]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,14,15]}],"complexes":["PEBP1/15-lipoxygenase complex","IL-17RA–Act1 complex","circPOLR2A–UBE3C–PEBP1 complex"],"partners":["RAF1","MAP2K1","BRAF","GRK2","ALOX15","MAP1LC3B","PYCARD","RIPK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30086","full_name":"Phosphatidylethanolamine-binding protein 1","aliases":["HCNPpp","Neuropolypeptide h3","Prostatic-binding protein","Raf kinase inhibitor protein","RKIP"],"length_aa":187,"mass_kda":21.1,"function":"Binds ATP, opioids and phosphatidylethanolamine. Has lower affinity for phosphatidylinositol and phosphatidylcholine. Serine protease inhibitor which inhibits thrombin, neuropsin and chymotrypsin but not trypsin, tissue type plasminogen activator and elastase (By similarity). Inhibits the kinase activity of RAF1 by inhibiting its activation and by dissociating the RAF1/MEK complex and acting as a competitive inhibitor of MEK phosphorylation HCNP may be involved in the function of the presynaptic cholinergic neurons of the central nervous system. HCNP increases the production of choline acetyltransferase but not acetylcholinesterase. Seems to be mediated by a specific receptor (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P30086/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEBP1","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEBP1","total_profiled":1310},"omim":[{"mim_id":"610173","title":"MICRO RNA 10A; MIR10A","url":"https://www.omim.org/entry/610173"},{"mim_id":"604834","title":"TANK-BINDING KINASE 1; TBK1","url":"https://www.omim.org/entry/604834"},{"mim_id":"604591","title":"PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1; 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oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597358","citation_count":17,"is_preprint":false},{"pmid":"30244142","id":"PMC_30244142","title":"Identification and expression analysis of phosphatidy ethanolamine-binding protein (PEBP) gene family in cotton.","date":"2018","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30244142","citation_count":17,"is_preprint":false},{"pmid":"23601922","id":"PMC_23601922","title":"Raf kinase inhibitor protein (RKIP) and phospho-RKIP expression in melanomas.","date":"2013","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/23601922","citation_count":17,"is_preprint":false},{"pmid":"36291854","id":"PMC_36291854","title":"Understanding Mechanisms of RKIP Regulation to Improve the Development of New Diagnostic Tools.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36291854","citation_count":17,"is_preprint":false},{"pmid":"34669021","id":"PMC_34669021","title":"RNA-binding protein CELF1 promotes cardiac hypertrophy via interaction with PEBP1 in cardiomyocytes.","date":"2021","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/34669021","citation_count":16,"is_preprint":false},{"pmid":"34893811","id":"PMC_34893811","title":"Analysis of the PEBP gene family and identification of a novel FLOWERING LOCUS T orthologue in sugarcane.","date":"2022","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/34893811","citation_count":16,"is_preprint":false},{"pmid":"35366758","id":"PMC_35366758","title":"Genome-wide identification of PEBP gene family members in potato, their phylogenetic relationships, and expression patterns under heat stress.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35366758","citation_count":16,"is_preprint":false},{"pmid":"37205308","id":"PMC_37205308","title":"Cancer resistance via the downregulation of the tumor suppressors RKIP and PTEN expressions: therapeutic implications.","date":"2023","source":"Exploration of targeted anti-tumor therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37205308","citation_count":16,"is_preprint":false},{"pmid":"31628413","id":"PMC_31628413","title":"Identification and Characterization of the PEBP Family Genes in Moso Bamboo (Phyllostachys heterocycla).","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31628413","citation_count":16,"is_preprint":false},{"pmid":"37977422","id":"PMC_37977422","title":"AR/RKIP pathway mediates the inhibitory effects of icariin on renal fibrosis and endothelial-to-mesenchymal transition in type 2 diabetic nephropathy.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37977422","citation_count":16,"is_preprint":false},{"pmid":"29200875","id":"PMC_29200875","title":"RKIP reduction enhances radioresistance by activating the Shh signaling pathway in non-small-cell lung cancer.","date":"2017","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29200875","citation_count":16,"is_preprint":false},{"pmid":"37678654","id":"PMC_37678654","title":"Membrane regulation of 15LOX-1/PEBP1 complex prompts the generation of ferroptotic signals, oxygenated PEs.","date":"2023","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37678654","citation_count":15,"is_preprint":false},{"pmid":"34885208","id":"PMC_34885208","title":"A Functional Network Model of the Metastasis Suppressor PEBP1/RKIP and Its Regulators in Breast Cancer Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34885208","citation_count":15,"is_preprint":false},{"pmid":"36348434","id":"PMC_36348434","title":"Low expression of PEBP1P2 promotes metastasis of clear cell renal cell carcinoma by post-transcriptional regulation of PEBP1 and KLF13 mRNA.","date":"2022","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36348434","citation_count":15,"is_preprint":false},{"pmid":"32918615","id":"PMC_32918615","title":"Resveratrol binds and activates RKIP protein in colorectal cancer.","date":"2020","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/32918615","citation_count":14,"is_preprint":false},{"pmid":"24763848","id":"PMC_24763848","title":"Expression of Raf Kinase Inhibitor Protein (RKIP) is a predictor of uveal melanoma metastasis.","date":"2014","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24763848","citation_count":14,"is_preprint":false},{"pmid":"35086479","id":"PMC_35086479","title":"Florigen and its homologs of FT/CETS/PEBP/RKIP/YbhB family may be the enzymes of small molecule metabolism: review of the evidence.","date":"2022","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/35086479","citation_count":13,"is_preprint":false},{"pmid":"35203304","id":"PMC_35203304","title":"The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35203304","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51563,"output_tokens":6839,"usd":0.128637,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15658,"output_tokens":4641,"usd":0.097157,"stage2_stop_reason":"end_turn"},"total_usd":0.225794,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"RKIP (PEBP1) binds to Raf-1 and MEK in vitro and co-immunoprecipitates with Raf-1 and MEK from cell lysates, competitively disrupting the Raf-1/MEK interaction and thereby inhibiting MEK phosphorylation and ERK activation. RKIP is not a substrate for Raf-1 or MEK. Overexpression inhibits MEK/ERK/AP-1 activation; antisense or antibody microinjection activates MEK/ERK/AP-1.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation, confocal colocalization, reporter gene assay, antisense RNA/antibody microinjection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Y2H, Co-IP, in vitro binding, functional overexpression and loss-of-function), foundational paper replicated extensively\",\n      \"pmids\": [\"10490027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKC phosphorylates RKIP, causing release of Raf-1 and activation of MEK/ERK. The phosphorylated form of RKIP then binds to and inhibits G-protein-coupled receptor kinase 2 (GRK2), resulting in sustained G-protein signaling — establishing RKIP as a molecular switch between two distinct kinase-inhibitory states.\",\n      \"method\": \"Biochemical/pharmacological assays described in review citing primary experimental work\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic model supported by primary experimental data cited across multiple labs; abstracted here as a review summary, limiting direct method verification\",\n      \"pmids\": [\"15313400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RKIP interacts with B-Raf (in addition to Raf-1) and antagonizes its kinase activity. Yeast two-hybrid and co-immunoprecipitation confirmed RKIP–B-Raf interaction; ectopic RKIP expression reduced B-Raf kinase activity independently of its known inhibitory action on Raf-1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, kinase activity assay, ectopic overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Y2H and Co-IP plus functional kinase assay in same study\",\n      \"pmids\": [\"15782137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PEBP1 forms a complex with 15-lipoxygenase isoforms 15LO1 and 15LO2, altering their substrate specificity from free polyunsaturated fatty acids to phosphatidylethanolamine (PE), enabling generation of hydroperoxy-PE (HpETE-PE) — the proximate ferroptotic death signal. This PEBP1/15LO complex is required for ferroptotic cell death in airway epithelial cells, kidney epithelial cells, and neurons.\",\n      \"method\": \"Co-immunoprecipitation, lipidomic analysis (redox lipidomics), cell-based ferroptosis models (airway, renal, neuronal), genetic loss-of-function\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP of complex, substrate specificity assay, multiple independent cell/tissue models, replicated by subsequent studies\",\n      \"pmids\": [\"29053969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RKIP binds GSK3 proteins and maintains GSK3β protein levels and active form. RKIP depletion activates p38 MAPK which phosphorylates GSK3β at inhibitory T390, de-repressing GSK3β substrates cyclin D, β-catenin, SNAIL and SLUG, promoting cell-cycle progression and EMT.\",\n      \"method\": \"Co-immunoprecipitation, RKIP knockdown/overexpression, phosphorylation assays, Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing RKIP–GSK3 binding plus functional knockdown with defined phosphorylation readouts, single lab\",\n      \"pmids\": [\"21303975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RKIP inhibits breast tumor metastasis in part through a pathway involving let-7 miRNA, which suppresses let-7 targets HMGA2 and BACH1; BACH1 is a transcription factor that induces MMP1 expression and promotes bone metastasis genes (MMP1, OPN, CXCR4).\",\n      \"method\": \"Statistical analysis of tumor gene expression combined with experimental validation (overexpression, knockdown, reporter assays)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — experimental validation of pathway with multiple gene knockdowns and expression analysis, single lab\",\n      \"pmids\": [\"21873975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CDK5 phosphorylates RKIP at T42 in neurons, causing release of Raf-1. T42 phosphorylation also exposes the C-terminal motif 'KLYEQ', recognized by chaperone Hsc70, leading to chaperone-mediated autophagy (CMA) degradation of RKIP. This CDK5/RKIP/ERK pathway is activated in Parkinson's disease models, leading to ERK overactivation, S-phase re-entry, and neuronal loss.\",\n      \"method\": \"In vitro kinase assay (CDK5 phosphorylation), mutagenesis (T42), co-immunoprecipitation (Hsc70/RKIP), CMA degradation assay, PD mouse models and patient brain samples\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with mutagenesis, CMA degradation assay, validated in disease models; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25104559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEBP1 contains a functional LC3-interacting region (LIR) motif (WXXL) that mediates direct binding to PE-unconjugated LC3. PEBP1 overexpression inhibits starvation-induced autophagy by activating AKT–mTORC1 signaling and suppressing ULK1 activity. Mutation of the LIR motif (AXXA) disrupts LC3 binding but promotes rather than inhibits autophagy. Phosphorylation of PEBP1 at Ser153 dissociates the PEBP1–LC3 complex to allow autophagy induction.\",\n      \"method\": \"Co-immunoprecipitation, LIR motif mutagenesis, autophagy flux assays, AKT/mTORC1/ULK1 phosphorylation analysis, overexpression/knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding shown by Co-IP, functional mutagenesis of LIR motif, multiple pathway readouts, single lab\",\n      \"pmids\": [\"27540684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEBP1 interacts with both 15LO1 (proferroptotic) and the autophagic protein LC3, acting as a rheostat. The 15LO1-PEBP1-generated ferroptotic lipid 15-HpETE-PE promotes LC3-I lipidation to stimulate compensatory autophagy, protecting cells from ferroptotic death.\",\n      \"method\": \"Co-immunoprecipitation, lipidomic analysis, autophagy flux assays, human airway epithelial cell models, asthma patient samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of PEBP1 with both 15LO1 and LC3, functional lipidomic and autophagy readouts, validated in patient samples; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32513718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ferrostatin-1 (Fer-1) does not inhibit 15LOX alone, but effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows Fer-1 binds to the 15LOX/PEBP1 complex at three sites, disrupting allosteric motions required for catalysis.\",\n      \"method\": \"Biochemical inhibition assay (15LOX alone vs. complex), computational molecular docking/modeling, redox lipidomics in nine ferroptosis cell/tissue models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic activity assay distinguishing 15LOX alone from 15LOX/PEBP1 complex, computational binding analysis, replicated across nine models\",\n      \"pmids\": [\"33126055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEBP1 suppresses HIV-1 transcription and induces latency by de-phosphorylating Raf1/ERK/IκB and IKK/IκB signaling pathways, sequestering NF-κB in the cytoplasm and preventing transcriptional activation of HIV-1. Identified via genome-wide CRISPR-Cas9 knockout screen.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, phosphorylation assays, NF-κB nuclear translocation assays, HIV latency models (multiple cell lines + primary CD4+ T cells from ART patients)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased CRISPR screen plus mechanistic validation (phosphorylation assays, NF-κB localization) replicated in multiple latency models\",\n      \"pmids\": [\"32924251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RKIP directly binds ASC (apoptosis-associated speck-like protein containing a CARD domain) and competes with NLRP1, NLRP3, and NLRC4 for ASC interaction, thereby interrupting inflammasome assembly and activation and suppressing caspase-1 activation and IL-1β secretion.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown in THP-1 cells and primary macrophages, RKIP-deficient mouse models (Alum-induced peritonitis, Salmonella infection)\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding (Co-IP), competition assay, loss-of-function in primary cells and in vivo models with defined inflammasome readouts\",\n      \"pmids\": [\"32901127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RKIP directly interacts with IL-17RA and Act1 to promote formation of an IL-17R–Act1 complex, resulting in enhanced MAPK and NF-κB activation and downstream pro-inflammatory cytokine production. RKIP-deficient mice show ameliorated experimental autoimmune encephalomyelitis (EAE) specifically through the Th17-mediated pathway.\",\n      \"method\": \"Co-immunoprecipitation (RKIP with IL-17RA and Act1), RKIP-knockout mouse EAE model, adoptive T-cell transfer, cytokine production assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of ternary complex, RKIP-KO mouse with defined phenotype, adoptive transfer epistasis experiment\",\n      \"pmids\": [\"29674348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PEBP1 complexes with RIP3 kinase and inhibits necroptosis. When 15LOX is expressed at elevated levels (higher affinity for PEBP1), it competes with RIP3 to sequester PEBP1, switching cell death from necroptosis to ferroptosis. RIP3 K51A kinase-inactive mice show increased ferroptotic burden rescued by anti-ferroptotic compounds.\",\n      \"method\": \"Co-immunoprecipitation (PEBP1–RIP3), genetic models (Rip3K51A/K51A mice), redox lipidomics, biochemical competition assays, computational structural analysis\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP of novel PEBP1–RIP3 complex, in vivo genetic model with rescue by antiferroptotic drugs, multiple orthogonal methods\",\n      \"pmids\": [\"35101798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircPOLR2A interacts with both UBE3C and PEBP1 to form a ternary RNA-protein complex. UBE3C acts as a specific E3 ubiquitin ligase for PEBP1, and circPOLR2A enhances UBE3C-mediated ubiquitination and proteasomal degradation of PEBP1, thereby activating ERK signaling in clear cell renal cell carcinoma.\",\n      \"method\": \"RNA pull-down, mass spectrometry, RIP assay, Co-IP, Western blot (ubiquitination), rescue experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down and Co-IP demonstrate ternary complex; ubiquitination assay shows UBE3C as E3 ligase for PEBP1; single lab\",\n      \"pmids\": [\"35840930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIPK4 promotes proteasome-mediated degradation of PEBP1, thereby activating RAF1/MEK/ERK signaling. Suppression of PEBP1 degradation eliminates RIPK4-induced ERK activation and pancreatic cancer cell migration/invasion.\",\n      \"method\": \"High-throughput screening, Western blot (proteasome-mediated PEBP1 degradation), PEBP1 rescue experiments, migration/invasion assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments establishing causal link between RIPK4, PEBP1 degradation, and ERK pathway; single lab\",\n      \"pmids\": [\"29436617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human and bovine PEBP1 directly interact with morphine glucuronides (M3G and M6G) but not with morphine itself. M6G binds PEBP1 in a manner similar to the reference ligand phosphatidylethanolamine (PE), and PEBP1 displays similar affinity for PE, M6G, and M3G.\",\n      \"method\": \"Noncovalent electrospray ionization mass spectrometry (ESI-MS) of protein–ligand complexes\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical method (noncovalent MS) establishing direct binding, single lab single study\",\n      \"pmids\": [\"19564817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMR screening identified that the conserved ligand-binding pocket of RKIP binds phospholipid DHPE and three novel small-molecule ligands. Occupation of this pocket by DHPE regulates RKIP interaction with Raf-1; phosphorylation of RKIP at Ser-153 also regulates Raf-1 binding. The newly identified ligands did not affect RKIP–Raf-1 binding or RKIP phosphorylation.\",\n      \"method\": \"High-resolution heteronuclear NMR spectroscopy (chemical shift perturbation), compound library screening\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR-based binding characterization under near-physiological conditions; single lab\",\n      \"pmids\": [\"20463977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NMR mapping of human PEBP1 binding sites for GTP, FMN, and Raf-1 peptides (phosphorylated and non-phosphorylated) shows all ligands bind to the same region centered on the conserved ligand-binding pocket. Residues in the vicinity of, rather than within, the pocket appear required for Raf-1 interaction.\",\n      \"method\": \"NMR (chemical shift perturbation mapping), native mass spectrometry (KD measurement)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR plus MS for ligand binding characterization; single lab\",\n      \"pmids\": [\"22558375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PEBP1 is a substrate of calpain protease in vitro and in situ (brain injury model). PEBP1 also inhibits the chymotrypsin-like activity of the 26S proteasome by approximately 30% in vitro.\",\n      \"method\": \"In vitro proteolysis assay, in situ brain injury model, proteasome activity assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay plus in situ confirmation; single lab, single study\",\n      \"pmids\": [\"17018026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Computational simulations and lipidomic experiments show that membrane association of the 15LOX-1/PEBP1 complex triggers a conformational change facilitating access of stearoyl/arachidonoyl-PE (SAPE) substrate to the catalytic site. PEBP1 P112E mutation significantly impairs generation of the predominant ferroptotic product 15-HpETE-PE. The complex produces 15-HpETE-PE and 12-HpETE-PE at a 5:1 ratio.\",\n      \"method\": \"Computational molecular dynamics simulation, mutagenesis (P112E), LC-MS/MS lipidomics, membrane interaction assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with quantitative lipidomics and computational modeling in same study\",\n      \"pmids\": [\"37678654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FerroLOXIN-1 and -2 inhibit ferroptosis by specifically interacting with the 15LOX-2/PEBP1 complex: one compound alters substrate (ETE-PE) binding pose nonproductively, the other blocks the predominant oxygen channel, preventing ETE-PE peroxidation. Effects are not due to radical scavenging or iron chelation.\",\n      \"method\": \"Biochemical assay (15LOX/PEBP1 complex vs. 15LOX alone), computational docking, redox lipidomics, cell biology models, in vivo testing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mechanistic inhibitor studies with complex-specific biochemical assays, computational mechanism determination, and in vivo validation\",\n      \"pmids\": [\"37327313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDA-9/syntenin transcriptionally downregulates RKIP, and MDA-9 physically interacts with RKIP in melanoma cells. This interaction correlates with suppression of FAK and c-Src phosphorylation, blocking MDA-9-mediated FAK/c-Src complex formation needed for metastatic signaling.\",\n      \"method\": \"Tumor array, co-immunoprecipitation (MDA-9–RKIP), phosphorylation assays (FAK/c-Src), ectopic RKIP expression, in vivo tumor dissemination assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of novel RKIP–MDA-9 complex, functional phosphorylation readouts, in vivo validation; single lab\",\n      \"pmids\": [\"23066033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RKIP activates RhoA in an Erk2- and GEF-H1-dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression, thereby suppressing breast cancer cell invasion and metastasis.\",\n      \"method\": \"RhoA activity assay, co-immunoprecipitation, loss/gain-of-function (RKIP, GEF-H1), E-cadherin localization (imaging), CCL5 expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTPase activity assay, Co-IP, functional imaging and expression assays; single lab\",\n      \"pmids\": [\"34465801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELF1 (RNA-binding protein) directly binds to fragment 1 within the 3'UTR of PEBP1 mRNA (shown by RNA immunoprecipitation and biotin pull-down), post-transcriptionally suppressing PEBP1 protein expression without affecting PEBP1 mRNA levels. CELF1-mediated PEBP1 suppression activates MAPK signaling (Raf1, TAK1, ERK1/2, p38) and promotes cardiac hypertrophy.\",\n      \"method\": \"RNA immunoprecipitation (RIP), biotin RNA pull-down, dual-luciferase assay, CELF1 overexpression/depletion, TAC cardiac hypertrophy mouse model\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and biotin pull-down establish direct CELF1–PEBP1 mRNA interaction; functional cardiac model; single lab\",\n      \"pmids\": [\"34669021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RKIP negatively regulates MMP13 expression through the Erk2 signaling pathway in a transcription factor AP-1-independent manner, thereby inhibiting local breast cancer cell invasion. Loss/gain-of-function experiments show MMP13 as the causal downstream effector of RKIP-mediated invasion suppression.\",\n      \"method\": \"PCR-based screening, DNA microarray analysis, loss/gain-of-function (RKIP, MMP13), invasion assays, Erk2 pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combinatorial loss/gain-of-function establishes epistatic relationship; single lab\",\n      \"pmids\": [\"26308852\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEBP1/RKIP is a multifunctional scaffold inhibitor that (1) directly inhibits Raf-1 and B-Raf kinase activity by competitively blocking Raf–MEK interaction; (2) upon PKC phosphorylation at Ser153, switches to inhibit GRK2; (3) is phosphorylated by CDK5 at T42 triggering chaperone-mediated autophagy degradation; (4) forms a complex with 15-lipoxygenases (15LOX1/2) that redirects their substrate specificity toward phosphatidylethanolamines, generating pro-ferroptotic HpETE-PE death signals; (5) acts as a necroptosis-to-ferroptosis switch by competing with RIP3 for PEBP1 binding; (6) directly binds LC3 via an LIR motif to negatively regulate autophagy through AKT–mTORC1; (7) binds ASC to block NLRP1/3/NLRC4 inflammasome assembly; (8) interacts with IL-17RA/Act1 to promote IL-17R signaling; and (9) suppresses NF-κB-driven HIV transcription and can be degraded via UBE3C-mediated ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PEBP1 (RKIP) is a multifunctional small scaffold/regulatory protein that controls cell fate decisions by physically gating signaling kinases and lipid-oxidizing enzymes [#0, #3]. Its founding function is direct inhibition of the Raf/MEK/ERK cascade: it binds Raf-1 and MEK without being a substrate, competitively disrupting the Raf-1/MEK interaction to block MEK phosphorylation and ERK/AP-1 activation, and it similarly antagonizes B-Raf kinase activity [#0, #2]. This inhibitory grip is conditional — PKC phosphorylation releases Raf-1 and converts RKIP into a GRK2 inhibitor, establishing it as a phosphorylation-controlled molecular switch between two kinase-inhibitory states [#1]. Through ERK suppression, PEBP1 restrains tumor invasion and metastasis, acting via GSK3β stabilization, a let-7/HMGA2/BACH1 axis, RhoA/GEF-H1-dependent E-cadherin localization, and repression of MMP13 [#4, #5, #23, #25]. A distinct moonlighting activity emerged from its association with 15-lipoxygenases (15LO1/15LO2): the PEBP1/15LOX complex redirects enzyme substrate specificity from free fatty acids to phosphatidylethanolamine, generating the pro-ferroptotic death signal 15-HpETE-PE, a reaction requiring membrane-triggered conformational change and tunable by point mutations (P112E) and complex-selective inhibitors [#3, #20, #21]. PEBP1 thereby integrates death-pathway choices, competing with RIP3 to switch cells between necroptosis and ferroptosis and binding LC3 through an LIR motif to modulate autophagy via AKT–mTORC1 [#13, #7, #8]. It further suppresses inflammation by sequestering ASC to block NLRP1/3/NLRC4 inflammasome assembly, promotes IL-17R–Act1 signaling, and enforces HIV-1 latency by dephosphorylating Raf1/ERK and IKK/IκB to sequester NF-κB [#11, #12, #10]. PEBP1 protein levels are themselves controlled by phosphorylation-triggered chaperone-mediated autophagy (CDK5/T42), CELF1-mediated translational repression, and proteasomal degradation directed by UBE3C and RIPK4 [#6, #24, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the founding mechanism: how an endogenous protein restrains the Raf/MEK/ERK cascade, by showing RKIP physically competes Raf-1 away from MEK.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, Co-IP, and antisense/antibody microinjection in cells\",\n      \"pmids\": [\"10490027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of Raf-1/MEK competition\", \"Did not address regulation of RKIP itself\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Answered how RKIP inhibitory specificity is toggled, defining a PKC-phosphorylation switch from Raf-1 inhibition to GRK2 inhibition.\",\n      \"evidence\": \"Biochemical/pharmacological assays summarized in a review citing primary work\",\n      \"pmids\": [\"15313400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstracted from review, limiting direct method verification\", \"Stoichiometry and kinetics of the switch not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended Raf inhibition to B-Raf, showing the inhibitory scope is broader than Raf-1 alone.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and kinase activity assay with ectopic expression\",\n      \"pmids\": [\"15782137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether B-Raf and Raf-1 inhibition use identical interfaces\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified PEBP1 as a calpain substrate and a partial proteasome inhibitor, first hints that its stability and protease interplay are regulated.\",\n      \"evidence\": \"In vitro proteolysis, in situ brain injury model, proteasome activity assay\",\n      \"pmids\": [\"17018026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of calpain cleavage uncharacterized\", \"Mechanism of proteasome inhibition not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected RKIP loss to metastasis programs, defining downstream GSK3β-stabilizing and let-7/HMGA2/BACH1 axes that drive EMT and bone-metastasis genes.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression with phosphorylation readouts, and tumor expression analysis with reporter validation\",\n      \"pmids\": [\"21303975\", \"21873975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway models\", \"Direct versus indirect regulation of miRNA axis not fully separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapped the conserved ligand-binding pocket and additional partners (MDA-9/syntenin), clarifying that pocket occupancy and adjacent residues govern Raf-1 binding.\",\n      \"evidence\": \"NMR chemical shift mapping and native MS; Co-IP and phosphorylation/in vivo dissemination assays for MDA-9\",\n      \"pmids\": [\"22558375\", \"23066033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of GTP/FMN binding unresolved\", \"No crystal structure of Raf-1-bound complex\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed how PEBP1 levels are controlled, defining CDK5 phosphorylation at T42 that releases Raf-1 and triggers Hsc70-dependent chaperone-mediated autophagy degradation in neurodegeneration.\",\n      \"evidence\": \"In vitro CDK5 kinase assay, T42 mutagenesis, CMA degradation assay, PD mouse and patient samples\",\n      \"pmids\": [\"25104559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Generality of CMA route beyond neurons not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a non-kinase function, showing a functional LIR motif binds LC3 and negatively regulates autophagy via AKT–mTORC1/ULK1, gated by Ser153 phosphorylation.\",\n      \"evidence\": \"Co-IP, LIR mutagenesis (AXXA), autophagy flux, and pathway phosphorylation analysis\",\n      \"pmids\": [\"27540684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"How LC3 binding mechanistically alters AKT–mTORC1 not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the ferroptosis mechanism, showing the PEBP1/15LOX complex reprograms enzyme specificity toward phosphatidylethanolamine to generate the proximate HpETE-PE death signal.\",\n      \"evidence\": \"Co-IP, redox lipidomics, and genetic loss-of-function across airway, renal, and neuronal ferroptosis models\",\n      \"pmids\": [\"29053969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of substrate redirection not yet resolved at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded PEBP1 into immune signaling and degradation control, showing it builds the IL-17RA–Act1 complex and is degraded by RIPK4 to license RAF1/MEK/ERK-driven cancer invasion.\",\n      \"evidence\": \"Co-IP of ternary complex with RKIP-KO EAE/adoptive transfer; high-throughput screen with PEBP1 rescue and invasion assays\",\n      \"pmids\": [\"29674348\", \"29436617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RIPK4-directed degradation (E3 ligase) not identified in this study\", \"Direct versus scaffolded IL-17R assembly not structurally resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned PEBP1 as an integrator of death and inflammation, linking ferroptosis to compensatory autophagy, blocking inflammasome assembly via ASC, and enforcing HIV-1 latency by sequestering NF-κB.\",\n      \"evidence\": \"Co-IP/lipidomics/autophagy flux (15LO1–PEBP1–LC3); ASC competition with inflammasome readouts in macrophages and KO mice; genome-wide CRISPR screen plus NF-κB localization in latency models; complex-specific Fer-1 inhibition with computational docking\",\n      \"pmids\": [\"32513718\", \"32901127\", \"32924251\", \"33126055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein partitions among 15LOX, LC3, ASC, and NF-κB pathways in one cell is unresolved\", \"Inhibitor binding sites inferred computationally\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the death-mode switch and a degradation route, showing PEBP1 binds RIP3 to restrain necroptosis with 15LOX competing it toward ferroptosis, and that circPOLR2A/UBE3C ubiquitinates PEBP1.\",\n      \"evidence\": \"Co-IP, Rip3K51A mouse rescue, redox lipidomics, competition assays; RNA pull-down/MS/RIP and ubiquitination assays for UBE3C\",\n      \"pmids\": [\"35101798\", \"35840930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity-based competition thresholds in vivo not quantified\", \"circPOLR2A/UBE3C axis is single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the catalytic mechanism of the ferroptotic complex, showing membrane association triggers a conformational change enabling PE substrate access, and developed complex-selective inhibitors.\",\n      \"evidence\": \"Molecular dynamics, P112E mutagenesis with LC-MS/MS lipidomics; FerroLOXIN inhibitor studies with docking and in vivo testing\",\n      \"pmids\": [\"37678654\", \"37327313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure of the membrane-bound complex\", \"In vivo therapeutic window of inhibitors not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEBP1 dynamically partitions its single ligand pocket and interaction surfaces among competing partners (Raf/MEK, GRK2, 15LOX, LC3, ASC, RIP3) within one cell, and what governs that allocation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative competition model across partners\", \"No structure of PEBP1 in its alternative complexes\", \"Cell-type determinants of which function dominates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 1, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 12, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [16, 17, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 14, 15]}\n    ],\n    \"complexes\": [\n      \"PEBP1/15-lipoxygenase complex\",\n      \"IL-17RA–Act1 complex\",\n      \"circPOLR2A–UBE3C–PEBP1 complex\"\n    ],\n    \"partners\": [\n      \"RAF1\",\n      \"MAP2K1\",\n      \"BRAF\",\n      \"GRK2\",\n      \"ALOX15\",\n      \"MAP1LC3B\",\n      \"PYCARD\",\n      \"RIPK3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}