{"gene":"PEBP1","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":2017,"finding":"PEBP1 complexes with 15-lipoxygenase isoforms 15LO1 and 15LO2, changing their substrate competence from free polyunsaturated fatty acids to phosphatidylethanolamine (PE), enabling generation of hydroperoxy-PE (ferroptotic death signals). Insufficient GPX4 activity to reduce these hydroperoxy-PEs leads to ferroptosis.","method":"Co-immunoprecipitation, lipidomics, cell-based ferroptosis assays in multiple cell types, genetic manipulation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, replicated across three disease models, foundational mechanistic discovery","pmids":["29053969"],"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 modeling shows Fer-1 binds to the 15LOX/PEBP1 complex at three sites and disrupts allosteric motions required for catalysis.","method":"Biochemical inhibition assays, computational molecular modeling, redox lipidomics in nine ferroptosis models","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (biochemical, computational, nine cell/tissue models), Strong evidence","pmids":["33126055"],"is_preprint":false},{"year":2020,"finding":"PEBP1 acts as a rheostat between ferroptosis and autophagy: it interacts with both 15LO1 (proferroptotic) and the autophagic protein LC3, and the 15LO1-PEBP1-generated ferroptotic phospholipid 15-HpETE-PE promotes LC3-I lipidation to stimulate autophagy, which protects cells from ferroptotic death.","method":"Co-immunoprecipitation, lipid mass spectrometry, genetic knockdown/overexpression, patient HAEC samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, lipidomics, in vitro and patient-derived evidence","pmids":["32513718"],"is_preprint":false},{"year":2016,"finding":"PEBP1 contains a functional LC3-interacting region (LIR) motif (WXXL) and directly binds PE-unconjugated LC3 in cells. PEBP1 overexpression inhibits starvation-induced autophagy by activating AKT-MTORC1 signaling and suppressing ULK1 activity. Phosphorylation of PEBP1 at Ser153 dissociates LC3 from the PEBP1-LC3 complex, triggering autophagy induction.","method":"Co-immunoprecipitation, LIR motif mutagenesis (WXXL→AXXA), autophagy flux assays, kinase signaling analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding confirmed by mutagenesis and co-IP, mechanistic pathway dissection with multiple orthogonal methods","pmids":["27540684"],"is_preprint":false},{"year":2022,"finding":"PEBP1 complexes with RIP3 kinase and inhibits necroptosis. When 15LOX is elevated, its higher affinity enables it to sequester PEBP1 from RIP3, shifting cell death from necroptosis to ferroptosis via PUFA-PE oxidation; PEBP1 thus acts as a necroptosis-to-ferroptosis switch.","method":"Genetic (Rip3K51A/K51A mice), biochemical co-IP, redox lipidomics, computational modeling, in vivo irradiation and brain trauma models","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic, biochemical, computational, and in vivo approaches; multiple orthogonal methods","pmids":["35101798"],"is_preprint":false},{"year":2023,"finding":"Membrane association of the 15LOX-1/PEBP1 complex triggers a conformational change that facilitates access of SAPE substrates to the catalytic site; PEBP1 binding promotes tight interactions and induces further conformational changes enabling oxidation of SAPE to 15-HpETE-PE and 12-HpETE-PE. PEBP1 P112E mutation significantly affects ferroptotic signal generation.","method":"Computational molecular dynamics simulation, liquid chromatography-mass spectrometry, mutagenesis","journal":"Free radical biology & medicine","confidence":"High","confidence_rationale":"Tier 1 — computational simulations combined with LC-MS and mutagenesis providing structural-functional insight","pmids":["37678654"],"is_preprint":false},{"year":2023,"finding":"Two lead compounds FerroLOXIN-1 and FerroLOXIN-2 selectively inhibit ferroptosis by targeting the 15LOX-2/PEBP1 catalytic complex: one alters the binding pose of ETE-PE in a non-productive way, the other blocks the predominant oxygen channel, preventing ETE-PE peroxidation, without affecting biosynthesis of lipid mediators.","method":"Biochemical assays with custom compound library, redox lipidomics, computational analysis, in vitro and in vivo ferroptosis models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical, computational, in vitro and in vivo with mechanistic site-specific characterization","pmids":["37327313"],"is_preprint":false},{"year":2005,"finding":"RKIP (PEBP1) specifically interacts with B-Raf (in addition to Raf-1) and antagonizes B-Raf kinase activity; ectopic RKIP expression partially reverted B-Raf kinase-transformed melanoma cells. Effects on B-Raf were shown to be independent of RKIP's known inhibitory action on Raf-1.","method":"Yeast two-hybrid, co-immunoprecipitation, kinase activity assays, cell transformation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus yeast two-hybrid plus functional kinase assay, multiple orthogonal methods","pmids":["15782137"],"is_preprint":false},{"year":2014,"finding":"PEBP1 is a substrate of CDK5 in neurons; CDK5 phosphorylates PEBP1 at T42, causing release of Raf-1. T42 phosphorylation exposes the C-terminal motif 'KLYEQ', recognized by chaperone Hsc70, leading to chaperone-mediated autophagy (CMA) degradation of PEBP1, resulting in ERK/MAPK overactivation and neuronal death in Parkinson's disease models.","method":"In vitro kinase assay, mutagenesis, co-immunoprecipitation with Hsc70, CMA degradation assay, PD patient brain samples and animal models","journal":"Neurobiology of aging","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay, mutagenesis, co-IP, and validated in multiple PD models","pmids":["25104559"],"is_preprint":false},{"year":2020,"finding":"PEBP1 induces HIV latency by de-phosphorylating Raf1/ERK/IκB and IKK/IκB signaling pathways to sequester NF-κB in the cytoplasm, transcriptionally inactivating HIV-1. PEBP1 depletion reactivates HIV-1 in multiple latency models.","method":"Genome-wide CRISPR-Cas9 knockout screen, pathway signaling analysis, NF-κB nuclear translocation assays, primary CD4+ T cells from ART patients","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus mechanistic pathway validation plus primary patient cells","pmids":["32924251"],"is_preprint":false},{"year":2020,"finding":"RKIP (PEBP1) directly binds to ASC (apoptosis-associated speck-like protein containing a CARD) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thereby interrupting inflammasome assembly and activation.","method":"Co-immunoprecipitation, overexpression/knockdown in macrophages and THP-1 cells, in vivo mouse models of inflammasome-related disease","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated by co-IP, competition assay, validated in vivo","pmids":["32901127"],"is_preprint":false},{"year":2022,"finding":"CircPOLR2A interacts with both UBE3C and PEBP1, facilitating UBE3C-mediated ubiquitination and proteasomal degradation of PEBP1 protein; loss of PEBP1 activates the ERK signaling pathway to promote renal cell carcinoma progression.","method":"RNA pull-down, mass spectrometry, RIP, FISH, Co-IP, ubiquitination assay, rescue experiments","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods identifying UBE3C as E3 ligase for PEBP1 with functional rescue experiments","pmids":["35840930"],"is_preprint":false},{"year":2021,"finding":"Dihydroartemisinin (DHA) induces ferroptosis in HCC cells by promoting the formation of the PEBP1/15-LO complex and lipid peroxidation; DHA upregulates PEBP1 protein expression by inhibiting its ubiquitination degradation, without directly affecting 15-LO expression.","method":"Western blot, ferroptosis marker assays, PEBP1 knockdown rescue, ubiquitination assays, in vivo tumor models","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional assays with mechanistic ubiquitination link, single lab","pmids":["34925691"],"is_preprint":false},{"year":2018,"finding":"RIPK4 promotes pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway by inducing proteasome-mediated degradation of PEBP1; suppression of PEBP1 degradation eliminates RIPK4-induced RAF1/MEK/ERK activation.","method":"High-throughput screening, knockdown/overexpression, pathway inhibitor experiments, proteasome inhibition rescue","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 — functional rescue experiments with pathway analysis, single lab, no direct binding assay","pmids":["29436617"],"is_preprint":false},{"year":2012,"finding":"RKIP physically interacts with MDA-9/syntenin and suppresses FAK and c-Src phosphorylation; MDA-9 transcriptionally downregulates RKIP expression, and ectopic RKIP overrides MDA-9-mediated FAK/c-Src complex formation and metastatic signaling.","method":"Co-immunoprecipitation, tumor array, kinase phosphorylation assays, in vivo tumor dissemination model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional in vivo validation, single lab","pmids":["23066033"],"is_preprint":false},{"year":2006,"finding":"PEBP1 is a substrate of calpain both in vitro and in situ, confirmed in a brain injury model where calpain is activated; PEBP1 also inhibits the chymotrypsin-like activity of the proteasome by approximately 30%.","method":"In vitro proteomics calpain cleavage assay, brain injury model (in situ validation), proteasome activity assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro reconstitution plus in situ validation and enzymatic assay","pmids":["17018026"],"is_preprint":false},{"year":2010,"finding":"RKIP's conserved ligand-binding pocket binds phospholipid DHPE, and occupation of this pocket or phosphorylation at Ser-153 regulate RKIP's interaction with Raf-1. NMR screening identified three novel ligands binding to the RKIP pocket, with distinct properties from DHPE.","method":"Heteronuclear NMR spectroscopy, ligand binding assays, phosphorylation assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — NMR structural characterization with functional validation, near-physiological conditions","pmids":["20463977"],"is_preprint":false},{"year":2014,"finding":"RKIP structural analysis identifies an allosteric mechanism with three functional states: (1) binding and inhibiting Raf-1, (2) after Ser-153 phosphorylation, binding and inhibiting GRK2, and (3) a third state facilitating RKIP phosphorylation; pocket loop dynamics control transitions between these states.","method":"Structural analysis (review of crystal structures combined with functional data), phosphorylation assays","journal":"Critical reviews in oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — structural/biochemical review synthesizing existing data; model based on prior experimental evidence","pmids":["25597357"],"is_preprint":false},{"year":2021,"finding":"RKIP inhibits breast cancer cell invasion by stimulating RhoA anti-tumorigenic functions in an ERK2 and GEF-H1 dependent manner, enhancing E-cadherin membrane localization and inhibiting CCL5 expression.","method":"Knockdown/overexpression, RhoA activity assays, E-cadherin localization by imaging, CCL5 measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional pathway dissection with multiple readouts, single lab","pmids":["34465801"],"is_preprint":false},{"year":2012,"finding":"RKIP transcription is positively regulated by androgen/androgen receptor (AR): DHT increases RKIP promoter activity, AR binds to a putative androgen response element (ARE) in the RKIP promoter (validated by EMSA and ChIP), and castration reduces RKIP expression in mouse prostate in vivo.","method":"RT-PCR, Western blot, luciferase reporter assay, EMSA, ChIP assay, in vivo castration model","journal":"Cellular physiology and biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter, in vivo) establishing AR-mediated transcriptional regulation","pmids":["23095933"],"is_preprint":false},{"year":2021,"finding":"CELF1 RNA-binding protein directly binds to the 3'UTR fragment 1 of PEBP1 mRNA (shown by RNA immunoprecipitation and biotin pull-down), reducing PEBP1 protein expression post-transcriptionally without altering PEBP1 mRNA levels; CELF1-mediated PEBP1 reduction activates MAPK signaling (Raf1, TAK1, ERK1/2, p38) promoting cardiac hypertrophy.","method":"RNA immunoprecipitation (RIP), biotin pull-down, dual-luciferase assay, Western blot, in vivo cardiac hypertrophy model (TAC)","journal":"Cell and tissue research","confidence":"High","confidence_rationale":"Tier 1-2 — direct RNA-protein interaction validated by multiple biochemical methods with in vivo functional consequence","pmids":["34669021"],"is_preprint":false},{"year":2015,"finding":"RKIP negatively regulates CCL5 expression in breast cancer cells, thereby limiting tumor macrophage infiltration and inhibiting angiogenesis; in mouse allograft models, ectopic RKIP expression decreased tumor vasculature, macrophage infiltration, and lung metastases through CCL5 suppression.","method":"Loss- and gain-of-function approaches, in vivo mouse allograft model, CCL5 rescue experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo validation with specific pathway rescue, single lab","pmids":["26375811"],"is_preprint":false},{"year":2015,"finding":"RKIP reduces STAT3 phosphorylation in NPC cells by directly interacting with STAT3; RKIP overexpression attenuates and RKIP knockdown enhances STAT3 activation, promoting NPC invasion, metastasis, and EMT through STAT3 pathway activation.","method":"Co-immunoprecipitation, gain- and loss-of-function, STAT3 phosphorylation assays, in vivo xenograft metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional in vivo rescue, single lab","pmids":["25915430"],"is_preprint":false},{"year":2024,"finding":"XJB-5-131 protects chondrocytes from ferroptosis via restoring PEBP1 expression; the anti-ferroptotic effects of XJB-5-131 were abolished by the PEBP1 antagonist Locostatin, identifying PEBP1 as the functional downstream target. RNA sequencing and DMM surgical OA models were used.","method":"RNA sequencing, PEBP1 antagonist (Locostatin), in vitro ferroptosis assays, in vivo DMM mouse model, intra-articular injection","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological rescue with specific antagonist plus in vivo validation, single lab","pmids":["38304614"],"is_preprint":false}],"current_model":"PEBP1 (RKIP) is a multifunctional scaffold protein that: (1) complexes with 15-lipoxygenases to redirect their substrate specificity toward phosphatidylethanolamines, generating hydroperoxy-PE ferroptotic death signals; (2) can switch between binding 15LOX (pro-ferroptotic) or RIP3 (anti-necroptotic) depending on relative expression levels; (3) inhibits the Raf/MEK/ERK and NF-κB signaling pathways, acting as a metastasis suppressor and pro-apoptotic factor; (4) directly binds LC3 via an LIR motif to negatively regulate autophagy through AKT-MTORC1 activation, and is released upon Ser153 phosphorylation to permit autophagy; (5) undergoes CDK5-mediated phosphorylation at T42 leading to chaperone-mediated autophagy degradation; and (6) inhibits inflammasome assembly by competing with NLR proteins for ASC binding."},"narrative":{"teleology":[{"year":2005,"claim":"Extending PEBP1's known inhibition of Raf-1, the demonstration that it also directly binds and antagonizes B-Raf established PEBP1 as a general MAP kinase pathway inhibitor relevant to oncogenic B-Raf signaling in melanoma.","evidence":"Yeast two-hybrid, co-IP, and kinase assays in melanoma cells","pmids":["15782137"],"confidence":"High","gaps":["Structural basis of PEBP1–B-Raf interaction not resolved","Whether PEBP1 inhibits other Raf family members was not tested"]},{"year":2006,"claim":"Identification of PEBP1 as a calpain substrate and partial proteasome inhibitor revealed that PEBP1 levels are themselves actively regulated by proteolytic systems.","evidence":"In vitro calpain cleavage assay, brain injury model, proteasome activity assay","pmids":["17018026"],"confidence":"Medium","gaps":["Physiological significance of 30% proteasome inhibition unclear","Calpain cleavage site not mapped"]},{"year":2010,"claim":"NMR characterization of PEBP1's conserved ligand-binding pocket showed that phospholipid occupancy and Ser153 phosphorylation are competing regulatory inputs controlling Raf-1 interaction, providing a structural basis for PEBP1's partner-switching behavior.","evidence":"Heteronuclear NMR spectroscopy with ligand binding and phosphorylation assays","pmids":["20463977"],"confidence":"High","gaps":["In vivo confirmation that pocket occupancy regulates partner switching not demonstrated","Full-length complex structures not available"]},{"year":2012,"claim":"Two discoveries broadened PEBP1's regulatory context: androgen receptor was shown to transcriptionally activate PEBP1 via a promoter ARE, and PEBP1 was found to physically interact with MDA-9/syntenin to suppress FAK/Src metastatic signaling.","evidence":"ChIP and EMSA for AR binding; co-IP plus in vivo dissemination model for MDA-9 interaction","pmids":["23095933","23066033"],"confidence":"High","gaps":["Whether AR-dependent PEBP1 regulation is disrupted in castration-resistant prostate cancer not tested","MDA-9 interaction domain on PEBP1 not mapped"]},{"year":2014,"claim":"CDK5-mediated phosphorylation at T42 was shown to release Raf-1 and expose a CMA-targeting motif, providing the first mechanism for signal-dependent PEBP1 degradation and linking PEBP1 loss to ERK overactivation in Parkinson's disease neurodegeneration.","evidence":"In vitro kinase assay, mutagenesis, Hsc70 co-IP, CMA degradation assay in PD models and patient brain samples","pmids":["25104559"],"confidence":"High","gaps":["Whether blocking T42 phosphorylation is neuroprotective in vivo not demonstrated","Other kinases targeting T42 not excluded"]},{"year":2016,"claim":"Discovery that PEBP1 contains a functional LIR motif and directly binds LC3 to inhibit autophagy via AKT-MTORC1 activation established PEBP1 as a negative regulator of autophagy, with Ser153 phosphorylation serving as the release switch.","evidence":"Co-IP, LIR motif mutagenesis (WXXL→AXXA), autophagy flux assays","pmids":["27540684"],"confidence":"High","gaps":["Kinase(s) responsible for Ser153 phosphorylation in this context not identified","Whether LC3 and Raf-1 binding are mutually exclusive not tested"]},{"year":2017,"claim":"The foundational discovery that PEBP1 complexes with 15-lipoxygenases to switch their substrate from free PUFAs to membrane phosphatidylethanolamine established the molecular mechanism of ferroptotic death signal generation.","evidence":"Co-IP, lipidomics, cell-based ferroptosis assays across multiple cell types and disease models","pmids":["29053969"],"confidence":"High","gaps":["Structural basis of how PEBP1 alters 15LOX substrate access not resolved at this point","Tissue specificity of the 15LOX/PEBP1 complex not explored"]},{"year":2020,"claim":"Three parallel advances defined PEBP1 as a multimodal cell-fate regulator: Fer-1 was shown to specifically target the 15LOX/PEBP1 complex rather than 15LOX alone; the ferroptotic product 15-HpETE-PE was found to stimulate LC3-I lipidation linking ferroptosis to autophagy; and PEBP1 was identified as a host factor maintaining HIV latency via NF-κB cytoplasmic sequestration.","evidence":"Biochemical inhibition and computational modeling across nine ferroptosis models; co-IP/lipidomics in patient HAECs; genome-wide CRISPR screen plus primary CD4+ T cells from ART patients","pmids":["33126055","32513718","32924251"],"confidence":"High","gaps":["Whether Fer-1 has clinical utility at the 15LOX/PEBP1 complex in vivo remains unclear","Mechanism by which 15-HpETE-PE promotes LC3-I lipidation not fully elucidated"]},{"year":2020,"claim":"PEBP1 was shown to directly bind ASC and competitively block NLR protein recruitment, establishing a role as an endogenous inflammasome assembly inhibitor.","evidence":"Co-IP, competition assays in macrophages and THP-1 cells, in vivo mouse inflammasome disease models","pmids":["32901127"],"confidence":"High","gaps":["Binding interface between PEBP1 and ASC not structurally defined","Whether PEBP1 regulates non-canonical inflammasomes not tested"]},{"year":2022,"claim":"Identification of RIP3 as a competitive PEBP1-binding partner showed that relative 15LOX/RIP3 expression levels determine whether PEBP1 drives ferroptosis or suppresses necroptosis, establishing PEBP1 as a cell-death mode switch.","evidence":"Genetic Rip3K51A/K51A mice, co-IP, redox lipidomics, computational modeling, in vivo brain trauma models","pmids":["35101798"],"confidence":"High","gaps":["Quantitative binding affinities of PEBP1 for RIP3 versus 15LOX not measured biochemically","Whether other RIPK family members compete for PEBP1 not examined"]},{"year":2023,"claim":"Molecular dynamics simulations combined with mutagenesis revealed how PEBP1 binding to membrane-associated 15LOX-1 induces conformational changes granting SAPE substrate access, and enabled design of selective ferroptosis inhibitors (FerroLOXINs) targeting the catalytic complex.","evidence":"Computational MD simulation, LC-MS lipidomics, P112E mutagenesis, custom compound screening in vitro and in vivo","pmids":["37678654","37327313"],"confidence":"High","gaps":["No high-resolution experimental structure of the 15LOX/PEBP1 complex available","FerroLOXIN pharmacokinetics and therapeutic window in disease models not established"]},{"year":null,"claim":"How PEBP1 simultaneously integrates signals from its multiple partners (15LOX, RIP3, Raf-1, LC3, ASC, STAT3) in a single cell — particularly the quantitative rules governing partner selection beyond expression level — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution experimental structure of any PEBP1–partner complex","Quantitative, cell-type-specific partner occupancy model lacking","In vivo genetic separation-of-function mutants for individual PEBP1 interactions not generated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,5,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,9,10,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,9,13,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,4,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5]}],"complexes":["15LOX/PEBP1 ferroptotic complex"],"partners":["ALOX15","ALOX15B","BRAF","RAF1","RIPK3","MAP1LC3B","PYCARD","STAT3"],"other_free_text":[]},"mechanistic_narrative":"PEBP1 (also known as RKIP) is a phospholipid-binding scaffold protein that controls cell fate decisions by toggling between distinct binding partners in a phosphorylation-dependent manner. It complexes with 15-lipoxygenase isoforms to redirect their substrate specificity from free polyunsaturated fatty acids to esterified phosphatidylethanolamines, generating hydroperoxy-PE signals that execute ferroptosis when GPX4 activity is insufficient [PMID:29053969, PMID:37678654]; competition between 15LOX and RIP3 for PEBP1 binding determines whether cells undergo ferroptosis or necroptosis [PMID:35101798]. Independently, PEBP1 inhibits the Raf/MEK/ERK and NF-κB signaling cascades by directly binding Raf-1 and B-Raf kinases, functioning as a metastasis suppressor whose loss activates ERK-dependent proliferative and invasive programs [PMID:15782137, PMID:32924251]. PEBP1 also directly binds LC3 via a LIR motif to suppress autophagy through AKT-MTORC1 activation, a constraint relieved by Ser153 phosphorylation, and binds ASC to competitively block NLRP3/NLRC4 inflammasome assembly [PMID:27540684, PMID:32901127]."},"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; PEBP1","url":"https://www.omim.org/entry/604591"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":2060.5},{"tissue":"liver","ntpm":1946.9}],"url":"https://www.proteinatlas.org/search/PEBP1"},"hgnc":{"alias_symbol":["RKIP","HCNP","PEBP"],"prev_symbol":["PBP"]},"alphafold":{"accession":"P30086","domains":[{"cath_id":"3.90.280.10","chopping":"4-183","consensus_level":"high","plddt":97.924,"start":4,"end":183}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30086","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30086-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30086-F1-predicted_aligned_error_v6.png","plddt_mean":97.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEBP1","jax_strain_url":"https://www.jax.org/strain/search?query=PEBP1"},"sequence":{"accession":"P30086","fasta_url":"https://rest.uniprot.org/uniprotkb/P30086.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30086/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30086"}},"corpus_meta":[{"pmid":"29053969","id":"PMC_29053969","title":"PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29053969","citation_count":758,"is_preprint":false},{"pmid":"21642442","id":"PMC_21642442","title":"Evolution of the PEBP gene family in plants: functional diversification in seed plant evolution.","date":"2011","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21642442","citation_count":209,"is_preprint":false},{"pmid":"14766752","id":"PMC_14766752","title":"RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14766752","citation_count":201,"is_preprint":false},{"pmid":"16170456","id":"PMC_16170456","title":"Phylogenomic analysis of the PEBP gene family in cereals.","date":"2005","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/16170456","citation_count":169,"is_preprint":false},{"pmid":"8517704","id":"PMC_8517704","title":"blaI and blaR1 regulate beta-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus.","date":"1993","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8517704","citation_count":134,"is_preprint":false},{"pmid":"1592809","id":"PMC_1592809","title":"Membrane intermediates in the peptidoglycan metabolism of Escherichia coli: possible roles of PBP 1b and PBP 3.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1592809","citation_count":129,"is_preprint":false},{"pmid":"20827424","id":"PMC_20827424","title":"The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-κB/Snail/RKIP/PTEN Circuit.","date":"2010","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20827424","citation_count":115,"is_preprint":false},{"pmid":"33126055","id":"PMC_33126055","title":"Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis.","date":"2020","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/33126055","citation_count":112,"is_preprint":false},{"pmid":"20933602","id":"PMC_20933602","title":"Dual role of NO donors in the reversal of tumor cell resistance and EMT: Downregulation of the NF-κB/Snail/YY1/RKIP circuitry.","date":"2010","source":"Nitric oxide : biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20933602","citation_count":109,"is_preprint":false},{"pmid":"19168644","id":"PMC_19168644","title":"Molecular and functional characterization of PEBP genes in barley reveal the diversification of their roles in flowering.","date":"2009","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19168644","citation_count":108,"is_preprint":false},{"pmid":"15782137","id":"PMC_15782137","title":"RKIP downregulates B-Raf kinase activity in melanoma cancer cells.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15782137","citation_count":107,"is_preprint":false},{"pmid":"10622376","id":"PMC_10622376","title":"Hippocampal cholinergic neurostimulating peptides (HCNP).","date":"2000","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/10622376","citation_count":102,"is_preprint":false},{"pmid":"23359513","id":"PMC_23359513","title":"RKIP: much more than Raf kinase inhibitory protein.","date":"2013","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23359513","citation_count":90,"is_preprint":false},{"pmid":"32513718","id":"PMC_32513718","title":"PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32513718","citation_count":89,"is_preprint":false},{"pmid":"28245474","id":"PMC_28245474","title":"MiR-543 Promotes Proliferation and Epithelial-Mesenchymal Transition in Prostate Cancer via Targeting RKIP.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28245474","citation_count":81,"is_preprint":false},{"pmid":"18508083","id":"PMC_18508083","title":"Structural basis of the honey bee PBP pheromone and pH-induced conformational change.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18508083","citation_count":71,"is_preprint":false},{"pmid":"22684368","id":"PMC_22684368","title":"Raf kinase inhibitor protein (RKIP) in cancer.","date":"2012","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/22684368","citation_count":69,"is_preprint":false},{"pmid":"12037323","id":"PMC_12037323","title":"The crystal structure of PEBP-2, a homologue of the PEBP/RKIP family.","date":"2002","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/12037323","citation_count":59,"is_preprint":false},{"pmid":"35840930","id":"PMC_35840930","title":"Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35840930","citation_count":59,"is_preprint":false},{"pmid":"29315556","id":"PMC_29315556","title":"KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29315556","citation_count":59,"is_preprint":false},{"pmid":"32580736","id":"PMC_32580736","title":"Bmi-1-induced miR-27a and miR-155 promote tumor metastasis and chemoresistance by targeting RKIP in gastric cancer.","date":"2020","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32580736","citation_count":57,"is_preprint":false},{"pmid":"23066033","id":"PMC_23066033","title":"Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23066033","citation_count":56,"is_preprint":false},{"pmid":"30149591","id":"PMC_30149591","title":"RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30149591","citation_count":55,"is_preprint":false},{"pmid":"25104559","id":"PMC_25104559","title":"CDK5-mediated phosphorylation and autophagy of RKIP regulate neuronal death in Parkinson's disease.","date":"2014","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/25104559","citation_count":52,"is_preprint":false},{"pmid":"15269597","id":"PMC_15269597","title":"Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP).","date":"2004","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/15269597","citation_count":49,"is_preprint":false},{"pmid":"21529916","id":"PMC_21529916","title":"Association of CRISP2, CCT8, PEBP1 mRNA abundance in sperm and sire conception rate in Holstein bulls.","date":"2011","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/21529916","citation_count":48,"is_preprint":false},{"pmid":"29436617","id":"PMC_29436617","title":"RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29436617","citation_count":46,"is_preprint":false},{"pmid":"27651238","id":"PMC_27651238","title":"RKIP suppresses the proliferation and metastasis of breast cancer cell lines through up-regulation of miR-185 targeting HMGA2.","date":"2016","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27651238","citation_count":46,"is_preprint":false},{"pmid":"25597354","id":"PMC_25597354","title":"Raf kinase inhibitory protein (RKIP) as a metastasis suppressor: regulation of signaling networks in cancer.","date":"2014","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597354","citation_count":45,"is_preprint":false},{"pmid":"27540684","id":"PMC_27540684","title":"PEBP1, a RAF kinase inhibitory protein, negatively regulates starvation-induced autophagy by direct interaction with LC3.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27540684","citation_count":44,"is_preprint":false},{"pmid":"34925691","id":"PMC_34925691","title":"Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15-LO.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/34925691","citation_count":43,"is_preprint":false},{"pmid":"26375811","id":"PMC_26375811","title":"RKIP regulates CCL5 expression to inhibit breast cancer invasion and metastasis by controlling macrophage infiltration.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26375811","citation_count":43,"is_preprint":false},{"pmid":"35149691","id":"PMC_35149691","title":"PEBP balances apoptosis and autophagy in whitefly upon arbovirus infection.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35149691","citation_count":40,"is_preprint":false},{"pmid":"28363333","id":"PMC_28363333","title":"Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.","date":"2017","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28363333","citation_count":38,"is_preprint":false},{"pmid":"27385268","id":"PMC_27385268","title":"Understanding perspectives of signalling mechanisms regulating PEBP1 function.","date":"2016","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/27385268","citation_count":37,"is_preprint":false},{"pmid":"35101798","id":"PMC_35101798","title":"Inactivation of RIP3 kinase sensitizes to 15LOX/PEBP1-mediated ferroptotic death.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35101798","citation_count":37,"is_preprint":false},{"pmid":"25597355","id":"PMC_25597355","title":"Survey of Raf kinase inhibitor protein (RKIP) in multiple cancer types.","date":"2014","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597355","citation_count":37,"is_preprint":false},{"pmid":"25597353","id":"PMC_25597353","title":"RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-κB/Snail/YY1/RKIP resistance-driver loop.","date":"2014","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597353","citation_count":37,"is_preprint":false},{"pmid":"30995398","id":"PMC_30995398","title":"Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design.","date":"2019","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30995398","citation_count":37,"is_preprint":false},{"pmid":"23632477","id":"PMC_23632477","title":"Geographic analysis of RKIP expression and its clinical relevance in colorectal cancer.","date":"2013","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23632477","citation_count":37,"is_preprint":false},{"pmid":"30150303","id":"PMC_30150303","title":"Mobility of Antiflorigen and PEBP mRNAs in Tomato-Tobacco Heterografts.","date":"2018","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30150303","citation_count":36,"is_preprint":false},{"pmid":"32901127","id":"PMC_32901127","title":"The inhibitor effect of RKIP on inflammasome activation and inflammasome-dependent diseases.","date":"2020","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32901127","citation_count":35,"is_preprint":false},{"pmid":"24392454","id":"PMC_24392454","title":"Overexpression of RKIP inhibits cell invasion in glioma cell lines through upregulation of miR-98.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24392454","citation_count":35,"is_preprint":false},{"pmid":"19342899","id":"PMC_19342899","title":"BRAF and RKIP are significantly decreased in cutaneous squamous cell carcinoma.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19342899","citation_count":34,"is_preprint":false},{"pmid":"31083461","id":"PMC_31083461","title":"Current Status of Raf Kinase Inhibitor Protein (RKIP) in Lung Cancer: Behind RTK Signaling.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31083461","citation_count":33,"is_preprint":false},{"pmid":"32924251","id":"PMC_32924251","title":"PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/32924251","citation_count":33,"is_preprint":false},{"pmid":"31766768","id":"PMC_31766768","title":"RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31766768","citation_count":32,"is_preprint":false},{"pmid":"7770119","id":"PMC_7770119","title":"Accumulation of hippocampal cholinergic neurostimulating peptide (HCNP)-related components in Hirano bodies.","date":"1995","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/7770119","citation_count":32,"is_preprint":false},{"pmid":"20853079","id":"PMC_20853079","title":"Implication of RAF and RKIP genes in urinary bladder cancer.","date":"2010","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/20853079","citation_count":32,"is_preprint":false},{"pmid":"26403261","id":"PMC_26403261","title":"The biological complexity of RKIP signaling in human cancers.","date":"2015","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26403261","citation_count":31,"is_preprint":false},{"pmid":"25915430","id":"PMC_25915430","title":"Reduction of RKIP expression promotes nasopharyngeal carcinoma invasion and metastasis by activating Stat3 signaling.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25915430","citation_count":31,"is_preprint":false},{"pmid":"35355228","id":"PMC_35355228","title":"Activation of RKIP Binding ASC Attenuates Neuronal Pyroptosis and Brain Injury via Caspase-1/GSDMD Signaling Pathway After Intracerebral Hemorrhage in Mice.","date":"2022","source":"Translational stroke research","url":"https://pubmed.ncbi.nlm.nih.gov/35355228","citation_count":31,"is_preprint":false},{"pmid":"23095933","id":"PMC_23095933","title":"Transcriptional regulation of RKIP expression by androgen in prostate cells.","date":"2012","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23095933","citation_count":31,"is_preprint":false},{"pmid":"32632129","id":"PMC_32632129","title":"Downregulation of RKIP promotes radioresistance of nasopharyngeal carcinoma by activating NRF2/NQO1 axis via downregulating miR-450b-5p.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32632129","citation_count":30,"is_preprint":false},{"pmid":"25108669","id":"PMC_25108669","title":"RKIP Regulates Neural Cell Apoptosis Induced by Exposure to Microwave Radiation Partly Through the MEK/ERK/CREB Pathway.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25108669","citation_count":30,"is_preprint":false},{"pmid":"28476134","id":"PMC_28476134","title":"Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma.","date":"2017","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/28476134","citation_count":28,"is_preprint":false},{"pmid":"25337233","id":"PMC_25337233","title":"Correlation of RKIP, STAT3 and cyclin D1 expression in pathogenesis of gastric cancer.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25337233","citation_count":28,"is_preprint":false},{"pmid":"20463977","id":"PMC_20463977","title":"Characterization of the Raf kinase inhibitory protein (RKIP) binding pocket: NMR-based screening identifies small-molecule ligands.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20463977","citation_count":28,"is_preprint":false},{"pmid":"32194149","id":"PMC_32194149","title":"Circular RNA MTO1 suppresses tumorigenesis of gastric carcinoma by sponging miR-3200-5p and targeting PEBP1.","date":"2020","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/32194149","citation_count":27,"is_preprint":false},{"pmid":"27552108","id":"PMC_27552108","title":"Characterization and Functional Analysis of PEBP Family Genes in Upland Cotton (Gossypium hirsutum L.).","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27552108","citation_count":27,"is_preprint":false},{"pmid":"36230521","id":"PMC_36230521","title":"The Role of RKIP in the Regulation of EMT in the Tumor Microenvironment.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36230521","citation_count":26,"is_preprint":false},{"pmid":"29088399","id":"PMC_29088399","title":"Tulipa gesneriana and Lilium longiflorum PEBP Genes and Their Putative Roles in Flowering Time Control.","date":"2018","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29088399","citation_count":26,"is_preprint":false},{"pmid":"20370618","id":"PMC_20370618","title":"Viral infection and cancer: the NF-kappaB/Snail/RKIP loop regulates target cell sensitivity to apoptosis by cytotoxic lymphocytes.","date":"2010","source":"Critical reviews in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20370618","citation_count":26,"is_preprint":false},{"pmid":"38030964","id":"PMC_38030964","title":"Penicillin-binding protein (PBP) inhibitor development: A 10-year chemical perspective.","date":"2023","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38030964","citation_count":24,"is_preprint":false},{"pmid":"9139244","id":"PMC_9139244","title":"Demonstration and characterization of hippocampal cholinergic neurostimulating peptide (HCNP) processing enzyme activity in rat hippocampus.","date":"1996","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/9139244","citation_count":24,"is_preprint":false},{"pmid":"25597357","id":"PMC_25597357","title":"RKIP structure drives its function: a three-state model for regulation of RKIP.","date":"2014","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597357","citation_count":22,"is_preprint":false},{"pmid":"25597360","id":"PMC_25597360","title":"Raf kinase inhibitory protein (RKIP): functional pleiotropy in the mammalian brain.","date":"2014","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25597360","citation_count":22,"is_preprint":false},{"pmid":"37298136","id":"PMC_37298136","title":"Genome-Wide Identification of PEBP Gene Family in Solanum lycopersicum.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37298136","citation_count":22,"is_preprint":false},{"pmid":"17018026","id":"PMC_17018026","title":"Identification and characterization of PEBP as a calpain substrate.","date":"2006","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17018026","citation_count":22,"is_preprint":false},{"pmid":"18329792","id":"PMC_18329792","title":"RKIP and BRAF aberrations in human nasal polyps and the adjacent turbinate mucosae.","date":"2008","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/18329792","citation_count":22,"is_preprint":false},{"pmid":"25962787","id":"PMC_25962787","title":"Ibudilast reverses the decrease in the synaptic signaling protein phosphatidylethanolamine-binding protein 1 (PEBP1) produced by chronic methamphetamine intake in rats.","date":"2015","source":"Drug and alcohol dependence","url":"https://pubmed.ncbi.nlm.nih.gov/25962787","citation_count":22,"is_preprint":false},{"pmid":"34944867","id":"PMC_34944867","title":"RKIP Pleiotropic Activities in Cancer and Inflammatory Diseases: Role in Immunity.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34944867","citation_count":21,"is_preprint":false},{"pmid":"30311562","id":"PMC_30311562","title":"Linking Autophagy and the Dysregulated NFκB/ SNAIL/YY1/RKIP/PTEN Loop in Cancer: Therapeutic Implications.","date":"2018","source":"Critical reviews in oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30311562","citation_count":21,"is_preprint":false},{"pmid":"8930956","id":"PMC_8930956","title":"Possible implication of hippocampal cholinergic neurostimulating peptide (HCNP)-related components in Hirano body formation.","date":"1996","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/8930956","citation_count":21,"is_preprint":false},{"pmid":"38304614","id":"PMC_38304614","title":"XJB-5-131 protects chondrocytes from ferroptosis to alleviate osteoarthritis progression via restoring Pebp1 expression.","date":"2024","source":"Journal of orthopaedic translation","url":"https://pubmed.ncbi.nlm.nih.gov/38304614","citation_count":20,"is_preprint":false},{"pmid":"39710830","id":"PMC_39710830","title":"Semaglutide protects against diabetes-associated cardiac inflammation via Sirt3-dependent RKIP pathway.","date":"2024","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39710830","citation_count":20,"is_preprint":false},{"pmid":"8824905","id":"PMC_8824905","title":"Distribution of hippocampal cholinergic neurostimulating peptide (HCNP)-like immunoreactivity in organs and tissues of young Wistar rats.","date":"1996","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8824905","citation_count":20,"is_preprint":false},{"pmid":"19705086","id":"PMC_19705086","title":"Downregulation of PEBP1 in rat brain cortex in hypoxia.","date":"2009","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/19705086","citation_count":20,"is_preprint":false},{"pmid":"8720492","id":"PMC_8720492","title":"Distribution of hippocampal cholinergic neurostimulating peptide (HCNP) immunoreactivity in the central nervous system of the rat.","date":"1996","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8720492","citation_count":20,"is_preprint":false},{"pmid":"37327313","id":"PMC_37327313","title":"Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37327313","citation_count":19,"is_preprint":false},{"pmid":"24420151","id":"PMC_24420151","title":"Clinical significance of RKIP mRNA expression in non-small cell lung cancer.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24420151","citation_count":19,"is_preprint":false},{"pmid":"33622244","id":"PMC_33622244","title":"Genome-wide characterization of PEBP family genes in nine Rosaceae tree species and their expression analysis in P. mume.","date":"2021","source":"BMC ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/33622244","citation_count":19,"is_preprint":false},{"pmid":"8841981","id":"PMC_8841981","title":"Neuronal expression of hippocampal cholinergic neurostimulating peptide (HCNP)-precursor mRNA in rat brain.","date":"1996","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/8841981","citation_count":18,"is_preprint":false},{"pmid":"37894300","id":"PMC_37894300","title":"Cross-Talks between RKIP and YY1 through a Multilevel Bioinformatics Pan-Cancer Analysis.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37894300","citation_count":18,"is_preprint":false},{"pmid":"33151569","id":"PMC_33151569","title":"cMET promotes metastasis and epithelial-mesenchymal transition in colorectal carcinoma by repressing RKIP.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33151569","citation_count":18,"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":"34465801","id":"PMC_34465801","title":"The RhoA dependent anti-metastatic function of RKIP in breast cancer.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34465801","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":"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":"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":"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":"11287059","id":"PMC_11287059","title":"Age-dependent changes in HCNP-related antigen expression in the human hippocampus.","date":"2001","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11287059","citation_count":15,"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":14,"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":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},{"pmid":"34945007","id":"PMC_34945007","title":"Insights of RKIP-Derived Suppression of Prostate Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34945007","citation_count":13,"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":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50453,"output_tokens":5638,"usd":0.117964},"stage2":{"model":"claude-opus-4-6","input_tokens":9216,"output_tokens":3108,"usd":0.18567},"total_usd":0.303634,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"PEBP1 complexes with 15-lipoxygenase isoforms 15LO1 and 15LO2, changing their substrate competence from free polyunsaturated fatty acids to phosphatidylethanolamine (PE), enabling generation of hydroperoxy-PE (ferroptotic death signals). Insufficient GPX4 activity to reduce these hydroperoxy-PEs leads to ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, lipidomics, cell-based ferroptosis assays in multiple cell types, genetic manipulation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, replicated across three disease models, foundational mechanistic discovery\",\n      \"pmids\": [\"29053969\"],\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 modeling shows Fer-1 binds to the 15LOX/PEBP1 complex at three sites and disrupts allosteric motions required for catalysis.\",\n      \"method\": \"Biochemical inhibition assays, computational molecular modeling, redox lipidomics in nine ferroptosis models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (biochemical, computational, nine cell/tissue models), Strong evidence\",\n      \"pmids\": [\"33126055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEBP1 acts as a rheostat between ferroptosis and autophagy: it interacts with both 15LO1 (proferroptotic) and the autophagic protein LC3, and the 15LO1-PEBP1-generated ferroptotic phospholipid 15-HpETE-PE promotes LC3-I lipidation to stimulate autophagy, which protects cells from ferroptotic death.\",\n      \"method\": \"Co-immunoprecipitation, lipid mass spectrometry, genetic knockdown/overexpression, patient HAEC samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, lipidomics, in vitro and patient-derived evidence\",\n      \"pmids\": [\"32513718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PEBP1 contains a functional LC3-interacting region (LIR) motif (WXXL) and directly binds PE-unconjugated LC3 in cells. PEBP1 overexpression inhibits starvation-induced autophagy by activating AKT-MTORC1 signaling and suppressing ULK1 activity. Phosphorylation of PEBP1 at Ser153 dissociates LC3 from the PEBP1-LC3 complex, triggering autophagy induction.\",\n      \"method\": \"Co-immunoprecipitation, LIR motif mutagenesis (WXXL→AXXA), autophagy flux assays, kinase signaling analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding confirmed by mutagenesis and co-IP, mechanistic pathway dissection with multiple orthogonal methods\",\n      \"pmids\": [\"27540684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PEBP1 complexes with RIP3 kinase and inhibits necroptosis. When 15LOX is elevated, its higher affinity enables it to sequester PEBP1 from RIP3, shifting cell death from necroptosis to ferroptosis via PUFA-PE oxidation; PEBP1 thus acts as a necroptosis-to-ferroptosis switch.\",\n      \"method\": \"Genetic (Rip3K51A/K51A mice), biochemical co-IP, redox lipidomics, computational modeling, in vivo irradiation and brain trauma models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic, biochemical, computational, and in vivo approaches; multiple orthogonal methods\",\n      \"pmids\": [\"35101798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Membrane association of the 15LOX-1/PEBP1 complex triggers a conformational change that facilitates access of SAPE substrates to the catalytic site; PEBP1 binding promotes tight interactions and induces further conformational changes enabling oxidation of SAPE to 15-HpETE-PE and 12-HpETE-PE. PEBP1 P112E mutation significantly affects ferroptotic signal generation.\",\n      \"method\": \"Computational molecular dynamics simulation, liquid chromatography-mass spectrometry, mutagenesis\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — computational simulations combined with LC-MS and mutagenesis providing structural-functional insight\",\n      \"pmids\": [\"37678654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two lead compounds FerroLOXIN-1 and FerroLOXIN-2 selectively inhibit ferroptosis by targeting the 15LOX-2/PEBP1 catalytic complex: one alters the binding pose of ETE-PE in a non-productive way, the other blocks the predominant oxygen channel, preventing ETE-PE peroxidation, without affecting biosynthesis of lipid mediators.\",\n      \"method\": \"Biochemical assays with custom compound library, redox lipidomics, computational analysis, in vitro and in vivo ferroptosis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical, computational, in vitro and in vivo with mechanistic site-specific characterization\",\n      \"pmids\": [\"37327313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RKIP (PEBP1) specifically interacts with B-Raf (in addition to Raf-1) and antagonizes B-Raf kinase activity; ectopic RKIP expression partially reverted B-Raf kinase-transformed melanoma cells. Effects on B-Raf were shown to be independent of RKIP's known inhibitory action on Raf-1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, kinase activity assays, cell transformation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus yeast two-hybrid plus functional kinase assay, multiple orthogonal methods\",\n      \"pmids\": [\"15782137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PEBP1 is a substrate of CDK5 in neurons; CDK5 phosphorylates PEBP1 at T42, causing release of Raf-1. T42 phosphorylation exposes the C-terminal motif 'KLYEQ', recognized by chaperone Hsc70, leading to chaperone-mediated autophagy (CMA) degradation of PEBP1, resulting in ERK/MAPK overactivation and neuronal death in Parkinson's disease models.\",\n      \"method\": \"In vitro kinase assay, mutagenesis, co-immunoprecipitation with Hsc70, CMA degradation assay, PD patient brain samples and animal models\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay, mutagenesis, co-IP, and validated in multiple PD models\",\n      \"pmids\": [\"25104559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PEBP1 induces HIV latency by de-phosphorylating Raf1/ERK/IκB and IKK/IκB signaling pathways to sequester NF-κB in the cytoplasm, transcriptionally inactivating HIV-1. PEBP1 depletion reactivates HIV-1 in multiple latency models.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen, pathway signaling analysis, NF-κB nuclear translocation assays, primary CD4+ T cells from ART patients\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus mechanistic pathway validation plus primary patient cells\",\n      \"pmids\": [\"32924251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RKIP (PEBP1) directly binds to ASC (apoptosis-associated speck-like protein containing a CARD) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thereby interrupting inflammasome assembly and activation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown in macrophages and THP-1 cells, in vivo mouse models of inflammasome-related disease\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by co-IP, competition assay, validated in vivo\",\n      \"pmids\": [\"32901127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircPOLR2A interacts with both UBE3C and PEBP1, facilitating UBE3C-mediated ubiquitination and proteasomal degradation of PEBP1 protein; loss of PEBP1 activates the ERK signaling pathway to promote renal cell carcinoma progression.\",\n      \"method\": \"RNA pull-down, mass spectrometry, RIP, FISH, Co-IP, ubiquitination assay, rescue experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods identifying UBE3C as E3 ligase for PEBP1 with functional rescue experiments\",\n      \"pmids\": [\"35840930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Dihydroartemisinin (DHA) induces ferroptosis in HCC cells by promoting the formation of the PEBP1/15-LO complex and lipid peroxidation; DHA upregulates PEBP1 protein expression by inhibiting its ubiquitination degradation, without directly affecting 15-LO expression.\",\n      \"method\": \"Western blot, ferroptosis marker assays, PEBP1 knockdown rescue, ubiquitination assays, in vivo tumor models\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional assays with mechanistic ubiquitination link, single lab\",\n      \"pmids\": [\"34925691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIPK4 promotes pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway by inducing proteasome-mediated degradation of PEBP1; suppression of PEBP1 degradation eliminates RIPK4-induced RAF1/MEK/ERK activation.\",\n      \"method\": \"High-throughput screening, knockdown/overexpression, pathway inhibitor experiments, proteasome inhibition rescue\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional rescue experiments with pathway analysis, single lab, no direct binding assay\",\n      \"pmids\": [\"29436617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RKIP physically interacts with MDA-9/syntenin and suppresses FAK and c-Src phosphorylation; MDA-9 transcriptionally downregulates RKIP expression, and ectopic RKIP overrides MDA-9-mediated FAK/c-Src complex formation and metastatic signaling.\",\n      \"method\": \"Co-immunoprecipitation, tumor array, kinase phosphorylation assays, in vivo tumor dissemination model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional in vivo validation, single lab\",\n      \"pmids\": [\"23066033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PEBP1 is a substrate of calpain both in vitro and in situ, confirmed in a brain injury model where calpain is activated; PEBP1 also inhibits the chymotrypsin-like activity of the proteasome by approximately 30%.\",\n      \"method\": \"In vitro proteomics calpain cleavage assay, brain injury model (in situ validation), proteasome activity assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution plus in situ validation and enzymatic assay\",\n      \"pmids\": [\"17018026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RKIP's conserved ligand-binding pocket binds phospholipid DHPE, and occupation of this pocket or phosphorylation at Ser-153 regulate RKIP's interaction with Raf-1. NMR screening identified three novel ligands binding to the RKIP pocket, with distinct properties from DHPE.\",\n      \"method\": \"Heteronuclear NMR spectroscopy, ligand binding assays, phosphorylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural characterization with functional validation, near-physiological conditions\",\n      \"pmids\": [\"20463977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RKIP structural analysis identifies an allosteric mechanism with three functional states: (1) binding and inhibiting Raf-1, (2) after Ser-153 phosphorylation, binding and inhibiting GRK2, and (3) a third state facilitating RKIP phosphorylation; pocket loop dynamics control transitions between these states.\",\n      \"method\": \"Structural analysis (review of crystal structures combined with functional data), phosphorylation assays\",\n      \"journal\": \"Critical reviews in oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural/biochemical review synthesizing existing data; model based on prior experimental evidence\",\n      \"pmids\": [\"25597357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RKIP inhibits breast cancer cell invasion by stimulating RhoA anti-tumorigenic functions in an ERK2 and GEF-H1 dependent manner, enhancing E-cadherin membrane localization and inhibiting CCL5 expression.\",\n      \"method\": \"Knockdown/overexpression, RhoA activity assays, E-cadherin localization by imaging, CCL5 measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional pathway dissection with multiple readouts, single lab\",\n      \"pmids\": [\"34465801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RKIP transcription is positively regulated by androgen/androgen receptor (AR): DHT increases RKIP promoter activity, AR binds to a putative androgen response element (ARE) in the RKIP promoter (validated by EMSA and ChIP), and castration reduces RKIP expression in mouse prostate in vivo.\",\n      \"method\": \"RT-PCR, Western blot, luciferase reporter assay, EMSA, ChIP assay, in vivo castration model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, reporter, in vivo) establishing AR-mediated transcriptional regulation\",\n      \"pmids\": [\"23095933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CELF1 RNA-binding protein directly binds to the 3'UTR fragment 1 of PEBP1 mRNA (shown by RNA immunoprecipitation and biotin pull-down), reducing PEBP1 protein expression post-transcriptionally without altering PEBP1 mRNA levels; CELF1-mediated PEBP1 reduction activates MAPK signaling (Raf1, TAK1, ERK1/2, p38) promoting cardiac hypertrophy.\",\n      \"method\": \"RNA immunoprecipitation (RIP), biotin pull-down, dual-luciferase assay, Western blot, in vivo cardiac hypertrophy model (TAC)\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct RNA-protein interaction validated by multiple biochemical methods with in vivo functional consequence\",\n      \"pmids\": [\"34669021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RKIP negatively regulates CCL5 expression in breast cancer cells, thereby limiting tumor macrophage infiltration and inhibiting angiogenesis; in mouse allograft models, ectopic RKIP expression decreased tumor vasculature, macrophage infiltration, and lung metastases through CCL5 suppression.\",\n      \"method\": \"Loss- and gain-of-function approaches, in vivo mouse allograft model, CCL5 rescue experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation with specific pathway rescue, single lab\",\n      \"pmids\": [\"26375811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RKIP reduces STAT3 phosphorylation in NPC cells by directly interacting with STAT3; RKIP overexpression attenuates and RKIP knockdown enhances STAT3 activation, promoting NPC invasion, metastasis, and EMT through STAT3 pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function, STAT3 phosphorylation assays, in vivo xenograft metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional in vivo rescue, single lab\",\n      \"pmids\": [\"25915430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"XJB-5-131 protects chondrocytes from ferroptosis via restoring PEBP1 expression; the anti-ferroptotic effects of XJB-5-131 were abolished by the PEBP1 antagonist Locostatin, identifying PEBP1 as the functional downstream target. RNA sequencing and DMM surgical OA models were used.\",\n      \"method\": \"RNA sequencing, PEBP1 antagonist (Locostatin), in vitro ferroptosis assays, in vivo DMM mouse model, intra-articular injection\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological rescue with specific antagonist plus in vivo validation, single lab\",\n      \"pmids\": [\"38304614\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEBP1 (RKIP) is a multifunctional scaffold protein that: (1) complexes with 15-lipoxygenases to redirect their substrate specificity toward phosphatidylethanolamines, generating hydroperoxy-PE ferroptotic death signals; (2) can switch between binding 15LOX (pro-ferroptotic) or RIP3 (anti-necroptotic) depending on relative expression levels; (3) inhibits the Raf/MEK/ERK and NF-κB signaling pathways, acting as a metastasis suppressor and pro-apoptotic factor; (4) directly binds LC3 via an LIR motif to negatively regulate autophagy through AKT-MTORC1 activation, and is released upon Ser153 phosphorylation to permit autophagy; (5) undergoes CDK5-mediated phosphorylation at T42 leading to chaperone-mediated autophagy degradation; and (6) inhibits inflammasome assembly by competing with NLR proteins for ASC binding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PEBP1 (also known as RKIP) is a phospholipid-binding scaffold protein that controls cell fate decisions by toggling between distinct binding partners in a phosphorylation-dependent manner. It complexes with 15-lipoxygenase isoforms to redirect their substrate specificity from free polyunsaturated fatty acids to esterified phosphatidylethanolamines, generating hydroperoxy-PE signals that execute ferroptosis when GPX4 activity is insufficient [PMID:29053969, PMID:37678654]; competition between 15LOX and RIP3 for PEBP1 binding determines whether cells undergo ferroptosis or necroptosis [PMID:35101798]. Independently, PEBP1 inhibits the Raf/MEK/ERK and NF-κB signaling cascades by directly binding Raf-1 and B-Raf kinases, functioning as a metastasis suppressor whose loss activates ERK-dependent proliferative and invasive programs [PMID:15782137, PMID:32924251]. PEBP1 also directly binds LC3 via a LIR motif to suppress autophagy through AKT-MTORC1 activation, a constraint relieved by Ser153 phosphorylation, and binds ASC to competitively block NLRP3/NLRC4 inflammasome assembly [PMID:27540684, PMID:32901127].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Extending PEBP1's known inhibition of Raf-1, the demonstration that it also directly binds and antagonizes B-Raf established PEBP1 as a general MAP kinase pathway inhibitor relevant to oncogenic B-Raf signaling in melanoma.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and kinase assays in melanoma cells\",\n      \"pmids\": [\"15782137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PEBP1–B-Raf interaction not resolved\", \"Whether PEBP1 inhibits other Raf family members was not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of PEBP1 as a calpain substrate and partial proteasome inhibitor revealed that PEBP1 levels are themselves actively regulated by proteolytic systems.\",\n      \"evidence\": \"In vitro calpain cleavage assay, brain injury model, proteasome activity assay\",\n      \"pmids\": [\"17018026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of 30% proteasome inhibition unclear\", \"Calpain cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"NMR characterization of PEBP1's conserved ligand-binding pocket showed that phospholipid occupancy and Ser153 phosphorylation are competing regulatory inputs controlling Raf-1 interaction, providing a structural basis for PEBP1's partner-switching behavior.\",\n      \"evidence\": \"Heteronuclear NMR spectroscopy with ligand binding and phosphorylation assays\",\n      \"pmids\": [\"20463977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation that pocket occupancy regulates partner switching not demonstrated\", \"Full-length complex structures not available\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two discoveries broadened PEBP1's regulatory context: androgen receptor was shown to transcriptionally activate PEBP1 via a promoter ARE, and PEBP1 was found to physically interact with MDA-9/syntenin to suppress FAK/Src metastatic signaling.\",\n      \"evidence\": \"ChIP and EMSA for AR binding; co-IP plus in vivo dissemination model for MDA-9 interaction\",\n      \"pmids\": [\"23095933\", \"23066033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AR-dependent PEBP1 regulation is disrupted in castration-resistant prostate cancer not tested\", \"MDA-9 interaction domain on PEBP1 not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CDK5-mediated phosphorylation at T42 was shown to release Raf-1 and expose a CMA-targeting motif, providing the first mechanism for signal-dependent PEBP1 degradation and linking PEBP1 loss to ERK overactivation in Parkinson's disease neurodegeneration.\",\n      \"evidence\": \"In vitro kinase assay, mutagenesis, Hsc70 co-IP, CMA degradation assay in PD models and patient brain samples\",\n      \"pmids\": [\"25104559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether blocking T42 phosphorylation is neuroprotective in vivo not demonstrated\", \"Other kinases targeting T42 not excluded\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that PEBP1 contains a functional LIR motif and directly binds LC3 to inhibit autophagy via AKT-MTORC1 activation established PEBP1 as a negative regulator of autophagy, with Ser153 phosphorylation serving as the release switch.\",\n      \"evidence\": \"Co-IP, LIR motif mutagenesis (WXXL→AXXA), autophagy flux assays\",\n      \"pmids\": [\"27540684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for Ser153 phosphorylation in this context not identified\", \"Whether LC3 and Raf-1 binding are mutually exclusive not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The foundational discovery that PEBP1 complexes with 15-lipoxygenases to switch their substrate from free PUFAs to membrane phosphatidylethanolamine established the molecular mechanism of ferroptotic death signal generation.\",\n      \"evidence\": \"Co-IP, lipidomics, cell-based ferroptosis assays across multiple cell types and disease models\",\n      \"pmids\": [\"29053969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how PEBP1 alters 15LOX substrate access not resolved at this point\", \"Tissue specificity of the 15LOX/PEBP1 complex not explored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three parallel advances defined PEBP1 as a multimodal cell-fate regulator: Fer-1 was shown to specifically target the 15LOX/PEBP1 complex rather than 15LOX alone; the ferroptotic product 15-HpETE-PE was found to stimulate LC3-I lipidation linking ferroptosis to autophagy; and PEBP1 was identified as a host factor maintaining HIV latency via NF-κB cytoplasmic sequestration.\",\n      \"evidence\": \"Biochemical inhibition and computational modeling across nine ferroptosis models; co-IP/lipidomics in patient HAECs; genome-wide CRISPR screen plus primary CD4+ T cells from ART patients\",\n      \"pmids\": [\"33126055\", \"32513718\", \"32924251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Fer-1 has clinical utility at the 15LOX/PEBP1 complex in vivo remains unclear\", \"Mechanism by which 15-HpETE-PE promotes LC3-I lipidation not fully elucidated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"PEBP1 was shown to directly bind ASC and competitively block NLR protein recruitment, establishing a role as an endogenous inflammasome assembly inhibitor.\",\n      \"evidence\": \"Co-IP, competition assays in macrophages and THP-1 cells, in vivo mouse inflammasome disease models\",\n      \"pmids\": [\"32901127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between PEBP1 and ASC not structurally defined\", \"Whether PEBP1 regulates non-canonical inflammasomes not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of RIP3 as a competitive PEBP1-binding partner showed that relative 15LOX/RIP3 expression levels determine whether PEBP1 drives ferroptosis or suppresses necroptosis, establishing PEBP1 as a cell-death mode switch.\",\n      \"evidence\": \"Genetic Rip3K51A/K51A mice, co-IP, redox lipidomics, computational modeling, in vivo brain trauma models\",\n      \"pmids\": [\"35101798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative binding affinities of PEBP1 for RIP3 versus 15LOX not measured biochemically\", \"Whether other RIPK family members compete for PEBP1 not examined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Molecular dynamics simulations combined with mutagenesis revealed how PEBP1 binding to membrane-associated 15LOX-1 induces conformational changes granting SAPE substrate access, and enabled design of selective ferroptosis inhibitors (FerroLOXINs) targeting the catalytic complex.\",\n      \"evidence\": \"Computational MD simulation, LC-MS lipidomics, P112E mutagenesis, custom compound screening in vitro and in vivo\",\n      \"pmids\": [\"37678654\", \"37327313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution experimental structure of the 15LOX/PEBP1 complex available\", \"FerroLOXIN pharmacokinetics and therapeutic window in disease models not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PEBP1 simultaneously integrates signals from its multiple partners (15LOX, RIP3, Raf-1, LC3, ASC, STAT3) in a single cell — particularly the quantitative rules governing partner selection beyond expression level — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution experimental structure of any PEBP1–partner complex\", \"Quantitative, cell-type-specific partner occupancy model lacking\", \"In vivo genetic separation-of-function mutants for individual PEBP1 interactions not generated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 5, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 9, 10, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 9, 13, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\n      \"15LOX/PEBP1 ferroptotic complex\"\n    ],\n    \"partners\": [\n      \"ALOX15\",\n      \"ALOX15B\",\n      \"BRAF\",\n      \"RAF1\",\n      \"RIPK3\",\n      \"MAP1LC3B\",\n      \"PYCARD\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}