{"gene":"EHBP1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2003,"finding":"EHBP1 interacts with EHD2 via NPF repeats in EHBP1 binding to the C-terminal EH domain of EHD2. EHBP1 contains a calponin homology (CH) domain that links clathrin-mediated endocytosis to the actin cytoskeleton. siRNA-mediated knockdown of EHBP1 inhibits transferrin endocytosis into EEA1-positive endosomes and GLUT4 endocytosis in adipocytes. Overexpression of EHBP1 mediates extensive actin reorganization.","method":"siRNA knockdown, co-immunoprecipitation, domain interaction mapping, cell-based endocytosis assays, actin reorganization imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal domain interaction mapping, siRNA knockdown with specific endocytic phenotype, and actin reorganization readout; replicated in multiple cell types in same study","pmids":["14676205"],"is_preprint":false},{"year":2004,"finding":"EHD1 interacts with EHBP1 through its EH domain, and both EHD1 and EHBP1 are required for perinuclear localization of GLUT4 and insulin-stimulated GLUT4 recycling in adipocytes. siRNA depletion of EHBP1 disrupts insulin-regulated GLUT4 movements and hexose transport. In contrast, EHD2 is not required for GLUT4 localization or translocation.","method":"siRNA knockdown, dominant-negative constructs, co-immunoprecipitation, immunofluorescence co-localization, glucose transport assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with specific GLUT4 trafficking phenotype and functional glucose transport readout, multiple orthogonal methods","pmids":["15247266"],"is_preprint":false},{"year":2010,"finding":"C. elegans EHBP-1 was identified as a direct binding partner of RAB-10 via yeast two-hybrid. EHBP-1-GFP co-localizes with RFP-RAB-10 on endosomal structures in intestinal and neuronal cells. Loss-of-function of ehbp-1 phenocopies rab-10 mutants in endosome morphology and cargo localization defects, including disrupted transport of membrane proteins to the plasma membrane. RAB-8 and RAB-10 show redundancy in non-polarized cells where EHBP-1 also functions.","method":"Yeast two-hybrid, in vivo co-localization (GFP/RFP), genetic loss-of-function mutants, cargo localization assays in C. elegans","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid binding, in vivo co-localization, genetic epistasis in multiple cell types in C. elegans ortholog","pmids":["20573983"],"is_preprint":false},{"year":2016,"finding":"In hepatocytes undergoing autophagy, Rab10 activity increases and Rab10 recruits EHBP1 and EHD2 to nascent autophagic membranes at the lipid droplet (LD) surface. Rab10 activation is essential for LC3 recruitment to the autophagosome and increases the association of EHBP1 and EHD2 with these membranes. Knockdown of Rab10 by siRNA or expression of a GTPase-defective Rab10 variant leads to LD accumulation, and EHBP1 and EHD2 together drive the engulfment of LDs during lipophagy.","method":"siRNA knockdown, GTPase-defective mutant expression, co-immunoprecipitation, fluorescence imaging, autophagy/lipophagy assays in hepatocytes","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific lipophagy phenotype, dominant-negative mutant, Co-IP showing complex formation, multiple orthogonal methods in one study","pmids":["28028537"],"is_preprint":false},{"year":2013,"finding":"Drosophila EHBP1 (dEHBP1) regulates the exocytosis of Scabrous (a positive regulator of Notch signaling), and its loss leads to supernumerary R8 photoreceptors due to defective lateral inhibition. dEHBP1 thus controls Notch signaling by trafficking distinct components (Scabrous vs. Delta) in different developmental contexts.","method":"Drosophila genetics (loss-of-function), cell fate analysis, epistasis with Notch pathway components, trafficking assays for Scabrous secretion","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with specific cellular phenotype and pathway placement (Notch/Scabrous), but single lab and Drosophila ortholog","pmids":["23788431"],"is_preprint":false},{"year":2014,"finding":"EHBP1 interacts with P-Rex1 (a guanine nucleotide exchange factor implicated in invasive growth) in PTEN-expressing prostate cancer cells, and EHBP1 is essential for the anti-invasive effect of atorvastatin. EHBP1 is involved in P2X7 signaling. Notably, the EHBP1-P-Rex1 interaction was not induced by extracellular ATP (the endogenous P2X7 ligand).","method":"Co-immunoprecipitation, siRNA knockdown, invasion assays, pharmacological inhibition","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP demonstrating interaction, siRNA knockdown with invasion phenotype, single lab","pmids":["24451147"],"is_preprint":false},{"year":2020,"finding":"The molecular mechanism of EHBP1 actin-binding activation was established: (1) EHBP1's N-terminal C2 domain associates with PI(3)P, PI(5)P, and phosphatidylserine, providing membrane targeting. (2) In the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular complex with the central calponin homology (CH) domain, auto-inhibiting actin binding. (3) Binding of active Rab8 to the bMERB domain relieves this autoinhibition, freeing the CH domain to interact with actin and drive membrane tubulation. Crystal/biochemical structures of the autoinhibited CH:bMERB complex and the active bMERB:Rab8 complex were determined and validated by structure-based mutagenesis.","method":"X-ray crystallography, in vitro biochemical binding assays, structure-based mutagenesis, actin binding assays, membrane tubulation assays, lipid binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both autoinhibited and active complexes, in vitro reconstitution, structure-based mutagenesis, multiple orthogonal methods in one rigorous study","pmids":["32826901"],"is_preprint":false},{"year":2024,"finding":"In Drosophila wing disc epithelium, Ehbp1 acts as a directional switch for polarized Wg/Wnt transport: AP-1 delivers Wg/Wnt basolaterally, and Ehbp1 competes with Wntless for AP-1 binding, thereby sequestering AP-1 and redirecting Wg/Wnt for apical delivery. Removing Ehbp1 coiled-coil motifs within its bMERB domain, or reducing Ehbp1 expression, leads to basolateral Wg/Wnt accumulation. This regulation of polarized Wnt delivery is conserved in vertebrates.","method":"Genetic epistasis (Drosophila), co-immunoprecipitation (AP-1 interaction), domain deletion mutants, cargo localization assays, vertebrate conservation experiments","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis, domain deletion mutagenesis, Co-IP showing AP-1 competition, and vertebrate conservation; single lab","pmids":["39402333"],"is_preprint":false},{"year":2024,"finding":"EHBP1 is critically involved in dendritic arbor formation in rat hippocampal neurons. A newly identified motif specific to chordate EHBP1 proteins mediates interaction with syndapin I (an F-BAR domain protein). This function does not require the Rab GTPase-binding domain but is strictly dependent on the syndapin I binding interface and syndapin I presence. EHBP1 forms ternary complexes with syndapin I and the actin nucleator Cobl at nascent dendritic branch sites. The C2 and CH domains of EHBP1 are also required for dendritic arborization.","method":"Gain-of-function and loss-of-function in primary rat hippocampal neurons, co-immunoprecipitation, domain deletion mutants, rescue experiments, live imaging of protein dynamics at dendritic branch sites","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-specific rescue experiments, live imaging at branch sites, multiple orthogonal methods in one rigorous study","pmids":["38129132"],"is_preprint":false},{"year":2025,"finding":"EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ (a fibrogenic effector) in the liver. EHBP1 deficiency disrupts the intracellular localization of retromer (a complex required for sortilin stabilization), thereby increasing hepatic cholesterol accumulation and MASH fibrosis. TNF-α/PPARα pathway suppresses EHBP1 in MASH.","method":"Loss-of-function and gain-of-function mouse models, mechanistic cell biology (retromer localization, PCSK9 secretion assays, LDLR degradation assays), immunofluorescence","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss- and gain-of-function, multiple mechanistic readouts (PCSK9 secretion, LDLR, TAZ, retromer localization), multiple orthogonal methods","pmids":["40015280"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, EHBP-1 localizes to recycling endosomes and captures RAB-10-positive lipoprotein exocytic carriers through its interaction with active RAB-10, promoting delivery of exocytic cargo to recycling endosomes. The mechanism requires synergy between EHBP-1's RAB-10-binding coiled-coil domain and its PI(4,5)P2-binding C2 domain. LST-6/DENND5 was identified as the GEF for RAB-10 in this post-Golgi pathway. After EHBP-1 capture, the exocyst complex carries out subsequent trafficking steps.","method":"C. elegans and mammalian cell genetics, live imaging, domain deletion mutants, GEF identification, epistasis with exocyst complex","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging of carrier capture, domain deletion mutants, genetic epistasis with GEF and exocyst; C. elegans ortholog, single lab","pmids":["39982707"],"is_preprint":false},{"year":2026,"finding":"EHBP1 localizes to the basal body and ciliary compartment of the primary cilium in human fibroblasts and RPE cells, and to the outer membrane of developing photoreceptors in retinal organoids. Dysfunction of INPP5E (due to patient mutations or CRISPR/Cas9 knockout) alters EHBP1 localization, placing EHBP1 in a ciliary functional module downstream of or regulated by INPP5E.","method":"Proximity-labeling proteomics (BioID), immunofluorescence localization in human fibroblasts/RPE, CRISPR/Cas9 knockout, patient-derived fibroblast analysis, retinal organoids","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proximity labeling identified the interaction, localization confirmed by imaging in multiple cell types, functional consequence shown via INPP5E loss-of-function; single lab","pmids":["41805112"],"is_preprint":false}],"current_model":"EHBP1 is an adaptor protein that links endosomal vesicle trafficking to the actin cytoskeleton by coupling active Rab GTPases (Rab8, Rab10) to EHD proteins and actin via its bMERB, CH, and C2 domains; its actin-binding CH domain is autoinhibited by intramolecular interaction with the bMERB domain and is activated upon Rab8 binding; EHBP1 functions in GLUT4 recycling, lipophagy, post-Golgi exocytic trafficking, Wnt polarized sorting, dendritic arborization (via a ternary complex with syndapin I and Cobl), hepatic cholesterol metabolism (through sortilin/PCSK9/LDLR pathway and retromer stabilization), and ciliary compartment organization downstream of INPP5E."},"narrative":{"mechanistic_narrative":"EHBP1 is a multidomain adaptor that couples endosomal membrane trafficking to the actin cytoskeleton by linking active Rab GTPases and EHD proteins to actin remodeling [PMID:14676205, PMID:20573983, PMID:32826901]. Its N-terminal C2 domain binds phosphoinositides and phosphatidylserine to target membranes, a central calponin homology (CH) domain binds actin and drives membrane tubulation, and a C-terminal bivalent Mical/EHBP Rab-binding (bMERB) domain engages active Rab8/Rab10; in the resting state the bMERB domain folds back onto the CH domain to autoinhibit actin binding, and Rab8 binding to bMERB relieves this autoinhibition to free the CH domain for actin engagement [PMID:32826901]. Through NPF-mediated binding to the EH domains of EHD1/EHD2, EHBP1 controls transferrin and GLUT4 endocytosis and is required for insulin-stimulated perinuclear GLUT4 recycling and hexose transport in adipocytes [PMID:14676205, PMID:15247266]. As a Rab10/Rab8 effector it captures exocytic and recycling carriers and supports cargo delivery to the plasma membrane, post-Golgi exocytic trafficking via a DENND5/LST-6-Rab10-exocyst axis, and Rab10-driven engulfment of lipid droplets during hepatic lipophagy together with EHD2 [PMID:20573983, PMID:28028537, PMID:39982707]. EHBP1 additionally directs polarized Wnt secretion by competing with Wntless for AP-1, mediates dendritic arbor formation through a chordate-specific motif that nucleates a ternary complex with syndapin I and the actin nucleator Cobl, and regulates hepatic cholesterol handling by promoting sortilin-mediated PCSK9 secretion and stabilizing retromer localization, with its loss increasing cholesterol accumulation and MASH fibrosis [PMID:39402333, PMID:38129132, PMID:40015280]. EHBP1 also localizes to the basal body and ciliary compartment downstream of INPP5E [PMID:41805112].","teleology":[{"year":2003,"claim":"Established EHBP1 as the molecular bridge connecting clathrin-mediated endocytosis to actin, answering how EHD proteins might couple vesicle traffic to the cytoskeleton.","evidence":"siRNA knockdown, domain interaction mapping and actin imaging linking EHBP1 NPF repeats to the EHD2 EH domain and a CH domain to actin","pmids":["14676205"],"confidence":"High","gaps":["Did not resolve how actin binding is regulated","Did not distinguish EHD1 vs EHD2 roles in specific cargo pathways"]},{"year":2004,"claim":"Defined a specific physiological role by showing EHBP1 and EHD1 are required for insulin-regulated GLUT4 recycling, distinguishing functional EHD partners.","evidence":"siRNA depletion, reciprocal Co-IP and glucose transport assays in adipocytes","pmids":["15247266"],"confidence":"High","gaps":["Did not identify the Rab GTPase driving this step","Mechanism of perinuclear localization unresolved"]},{"year":2010,"claim":"Identified EHBP1 as a direct Rab10 (and redundantly Rab8) effector, recasting it as a Rab-GTPase-linked trafficking factor.","evidence":"Yeast two-hybrid, in vivo co-localization and genetic epistasis in C. elegans","pmids":["20573983"],"confidence":"High","gaps":["Structural basis of Rab binding unknown","Did not connect Rab binding to actin regulation"]},{"year":2013,"claim":"Extended EHBP1 function to developmental signaling by showing it regulates exocytosis of the Notch modulator Scabrous.","evidence":"Drosophila loss-of-function genetics and trafficking assays","pmids":["23788431"],"confidence":"Medium","gaps":["Single lab and ortholog","Direct cargo-recognition mechanism not defined"]},{"year":2014,"claim":"Linked EHBP1 to P-Rex1 and anti-invasive statin action in prostate cancer, broadening its interactome.","evidence":"Co-IP, siRNA and invasion assays in PTEN-expressing prostate cancer cells","pmids":["24451147"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation","Functional relevance of P2X7 link unclear since interaction was ATP-independent"]},{"year":2016,"claim":"Placed EHBP1 in lipophagy, showing Rab10 recruits EHBP1 and EHD2 to lipid droplet membranes to drive LD engulfment.","evidence":"siRNA, GTPase-defective Rab10 mutant, Co-IP and lipophagy assays in hepatocytes","pmids":["28028537"],"confidence":"High","gaps":["How EHBP1/EHD2 shape autophagic membranes mechanistically not resolved","Connection to actin during lipophagy not directly tested"]},{"year":2020,"claim":"Solved the autoinhibition mechanism, explaining how Rab8 binding switches on EHBP1 actin binding and membrane tubulation.","evidence":"X-ray crystallography of autoinhibited CH:bMERB and active bMERB:Rab8 complexes with structure-based mutagenesis and in vitro assays","pmids":["32826901"],"confidence":"High","gaps":["In-cell dynamics of the switch not directly visualized","Whether other partners modulate the switch unknown"]},{"year":2024,"claim":"Revealed EHBP1 as a directional switch for polarized Wnt secretion by competing with Wntless for AP-1.","evidence":"Drosophila genetic epistasis, domain deletion, AP-1 Co-IP and vertebrate conservation","pmids":["39402333"],"confidence":"Medium","gaps":["Single lab","Quantitative basis of AP-1 competition not defined"]},{"year":2024,"claim":"Defined a Rab-independent neuronal function in dendritic arborization through a chordate-specific syndapin I-binding motif.","evidence":"Gain/loss-of-function, domain-specific rescue, Co-IP and live imaging in rat hippocampal neurons","pmids":["38129132"],"confidence":"High","gaps":["How the syndapin I/Cobl ternary complex nucleates actin at branch sites not fully resolved","Relationship to canonical Rab-dependent activity unclear"]},{"year":2025,"claim":"Established EHBP1 in hepatic cholesterol metabolism via sortilin/PCSK9/LDLR and retromer stabilization, with disease relevance to MASH fibrosis.","evidence":"Mouse loss/gain-of-function and mechanistic cell biology (PCSK9 secretion, LDLR degradation, retromer localization)","pmids":["40015280"],"confidence":"High","gaps":["Direct molecular link between EHBP1 and retromer not defined","How TNF-α/PPARα suppresses EHBP1 transcriptionally not resolved"]},{"year":2025,"claim":"Detailed the post-Golgi exocytic mechanism in which EHBP1 captures Rab10 carriers at recycling endosomes via coiled-coil and C2 synergy, handing off to the exocyst.","evidence":"C. elegans and mammalian genetics, live imaging, domain deletion and GEF (LST-6/DENND5) identification","pmids":["39982707"],"confidence":"Medium","gaps":["Single lab","Handoff to exocyst not mechanistically reconstituted"]},{"year":2026,"claim":"Positioned EHBP1 in a ciliary module regulated by INPP5E based on basal body/ciliary localization.","evidence":"BioID proximity labeling, immunofluorescence in fibroblasts/RPE, INPP5E CRISPR knockout and patient cells, retinal organoids","pmids":["41805112"],"confidence":"Medium","gaps":["Single lab","Direct functional role of EHBP1 in ciliary trafficking not established","Mechanism by which INPP5E controls EHBP1 localization unknown"]},{"year":null,"claim":"How EHBP1's distinct domain modules are selectively deployed across its diverse trafficking, signaling, and metabolic functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for how Rab-dependent vs Rab-independent (syndapin I) modes are partitioned across cell types","Whether ciliary and hepatic roles share a common molecular mechanism unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,6,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[11]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,2,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,7,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,7,8]}],"complexes":[],"partners":["EHD2","EHD1","RAB10","RAB8","SDPN1","COBL","AP-1","P-REX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NDI1","full_name":"EH domain-binding protein 1","aliases":[],"length_aa":1231,"mass_kda":140.0,"function":"May play a role in actin reorganization. Links clathrin-mediated endocytosis to the actin cytoskeleton. May act as Rab effector protein and play a role in vesicle trafficking (PubMed:14676205, PubMed:27552051). Required for perinuclear sorting and insulin-regulated recycling of SLC2A4/GLUT4 in adipocytes (By similarity)","subcellular_location":"Cytoplasm; Membrane; Endosome","url":"https://www.uniprot.org/uniprotkb/Q8NDI1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EHBP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EHBP1","total_profiled":1310},"omim":[{"mim_id":"619583","title":"EH DOMAIN-BINDING PROTEIN 1-LIKE 1; EHBP1L1","url":"https://www.omim.org/entry/619583"},{"mim_id":"611868","title":"PROSTATE CANCER, HEREDITARY, 12; HPC12","url":"https://www.omim.org/entry/611868"},{"mim_id":"609922","title":"EH DOMAIN-BINDING PROTEIN 1; EHBP1","url":"https://www.omim.org/entry/609922"},{"mim_id":"605890","title":"EH DOMAIN-CONTAINING 2; EHD2","url":"https://www.omim.org/entry/605890"},{"mim_id":"176807","title":"PROSTATE CANCER","url":"https://www.omim.org/entry/176807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EHBP1"},"hgnc":{"alias_symbol":["KIAA0903","NACSIN"],"prev_symbol":[]},"alphafold":{"accession":"Q8NDI1","domains":[{"cath_id":"2.60.40.150","chopping":"2-173","consensus_level":"high","plddt":88.6066,"start":2,"end":173},{"cath_id":"1.10.418.10","chopping":"446-566","consensus_level":"high","plddt":85.6342,"start":446,"end":566},{"cath_id":"1.10.287","chopping":"1126-1214","consensus_level":"medium","plddt":88.1293,"start":1126,"end":1214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDI1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDI1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDI1-F1-predicted_aligned_error_v6.png","plddt_mean":57.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EHBP1","jax_strain_url":"https://www.jax.org/strain/search?query=EHBP1"},"sequence":{"accession":"Q8NDI1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NDI1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NDI1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDI1"}},"corpus_meta":[{"pmid":"28028537","id":"PMC_28028537","title":"A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets.","date":"2016","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/28028537","citation_count":154,"is_preprint":false},{"pmid":"14676205","id":"PMC_14676205","title":"EHD2 and the novel EH domain binding protein EHBP1 couple endocytosis to the actin cytoskeleton.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14676205","citation_count":135,"is_preprint":false},{"pmid":"15247266","id":"PMC_15247266","title":"Role of EHD1 and EHBP1 in perinuclear sorting and insulin-regulated GLUT4 recycling in 3T3-L1 adipocytes.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15247266","citation_count":103,"is_preprint":false},{"pmid":"20573983","id":"PMC_20573983","title":"EHBP-1 functions with RAB-10 during endocytic recycling in Caenorhabditis elegans.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20573983","citation_count":102,"is_preprint":false},{"pmid":"24451147","id":"PMC_24451147","title":"Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells.","date":"2014","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24451147","citation_count":60,"is_preprint":false},{"pmid":"32826901","id":"PMC_32826901","title":"The mechanism of activation of the actin binding protein EHBP1 by Rab8 family members.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32826901","citation_count":28,"is_preprint":false},{"pmid":"32897609","id":"PMC_32897609","title":"Identification of a Novel EHBP1-MET Fusion in an Intrahepatic Cholangiocarcinoma Responding to Crizotinib.","date":"2020","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/32897609","citation_count":19,"is_preprint":false},{"pmid":"40015280","id":"PMC_40015280","title":"EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis.","date":"2025","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40015280","citation_count":14,"is_preprint":false},{"pmid":"23788431","id":"PMC_23788431","title":"Drosophila EHBP1 regulates Scabrous secretion during Notch-mediated lateral inhibition.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23788431","citation_count":11,"is_preprint":false},{"pmid":"32280856","id":"PMC_32280856","title":"EHBP1 SNPs, Their Haplotypes, and Gene-Environment Interactive Effects on Serum Lipid Levels.","date":"2020","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/32280856","citation_count":8,"is_preprint":false},{"pmid":"35113459","id":"PMC_35113459","title":"Spitz nevus with EHBP1-ALK fusion and distinctive membranous localization of ALK.","date":"2022","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35113459","citation_count":8,"is_preprint":false},{"pmid":"35559044","id":"PMC_35559044","title":"EHBP1, TUBB, and WWOX SNPs, Gene-Gene and Gene-Environment Interactions on Coronary Artery Disease and Ischemic Stroke.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35559044","citation_count":5,"is_preprint":false},{"pmid":"39982707","id":"PMC_39982707","title":"RAB-10 cooperates with EHBP-1 to capture vesicular carriers during post-Golgi exocytic trafficking.","date":"2025","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39982707","citation_count":5,"is_preprint":false},{"pmid":"39402333","id":"PMC_39402333","title":"Ehbp1 orchestrates orderly sorting of Wnt/Wingless to the basolateral and apical cell membranes.","date":"2024","source":"EMBO 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science","url":"https://pubmed.ncbi.nlm.nih.gov/41805112","citation_count":0,"is_preprint":false},{"pmid":"40004500","id":"PMC_40004500","title":"The Relationship of the Pathogenic Variant rs721048 in the Intron of the EHBP1 Gene with the Development of Prostate Cancer and Colorectal Cancer in the Kazakh Population.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40004500","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11280,"output_tokens":3843,"usd":0.045742,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11417,"output_tokens":3975,"usd":0.07823,"stage2_stop_reason":"end_turn"},"total_usd":0.123972,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"EHBP1 interacts with EHD2 via NPF repeats in EHBP1 binding to the C-terminal EH domain of EHD2. EHBP1 contains a calponin homology (CH) domain that links clathrin-mediated endocytosis to the actin cytoskeleton. siRNA-mediated knockdown of EHBP1 inhibits transferrin endocytosis into EEA1-positive endosomes and GLUT4 endocytosis in adipocytes. Overexpression of EHBP1 mediates extensive actin reorganization.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, domain interaction mapping, cell-based endocytosis assays, actin reorganization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal domain interaction mapping, siRNA knockdown with specific endocytic phenotype, and actin reorganization readout; replicated in multiple cell types in same study\",\n      \"pmids\": [\"14676205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EHD1 interacts with EHBP1 through its EH domain, and both EHD1 and EHBP1 are required for perinuclear localization of GLUT4 and insulin-stimulated GLUT4 recycling in adipocytes. siRNA depletion of EHBP1 disrupts insulin-regulated GLUT4 movements and hexose transport. In contrast, EHD2 is not required for GLUT4 localization or translocation.\",\n      \"method\": \"siRNA knockdown, dominant-negative constructs, co-immunoprecipitation, immunofluorescence co-localization, glucose transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with specific GLUT4 trafficking phenotype and functional glucose transport readout, multiple orthogonal methods\",\n      \"pmids\": [\"15247266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans EHBP-1 was identified as a direct binding partner of RAB-10 via yeast two-hybrid. EHBP-1-GFP co-localizes with RFP-RAB-10 on endosomal structures in intestinal and neuronal cells. Loss-of-function of ehbp-1 phenocopies rab-10 mutants in endosome morphology and cargo localization defects, including disrupted transport of membrane proteins to the plasma membrane. RAB-8 and RAB-10 show redundancy in non-polarized cells where EHBP-1 also functions.\",\n      \"method\": \"Yeast two-hybrid, in vivo co-localization (GFP/RFP), genetic loss-of-function mutants, cargo localization assays in C. elegans\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid binding, in vivo co-localization, genetic epistasis in multiple cell types in C. elegans ortholog\",\n      \"pmids\": [\"20573983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In hepatocytes undergoing autophagy, Rab10 activity increases and Rab10 recruits EHBP1 and EHD2 to nascent autophagic membranes at the lipid droplet (LD) surface. Rab10 activation is essential for LC3 recruitment to the autophagosome and increases the association of EHBP1 and EHD2 with these membranes. Knockdown of Rab10 by siRNA or expression of a GTPase-defective Rab10 variant leads to LD accumulation, and EHBP1 and EHD2 together drive the engulfment of LDs during lipophagy.\",\n      \"method\": \"siRNA knockdown, GTPase-defective mutant expression, co-immunoprecipitation, fluorescence imaging, autophagy/lipophagy assays in hepatocytes\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific lipophagy phenotype, dominant-negative mutant, Co-IP showing complex formation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28028537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila EHBP1 (dEHBP1) regulates the exocytosis of Scabrous (a positive regulator of Notch signaling), and its loss leads to supernumerary R8 photoreceptors due to defective lateral inhibition. dEHBP1 thus controls Notch signaling by trafficking distinct components (Scabrous vs. Delta) in different developmental contexts.\",\n      \"method\": \"Drosophila genetics (loss-of-function), cell fate analysis, epistasis with Notch pathway components, trafficking assays for Scabrous secretion\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with specific cellular phenotype and pathway placement (Notch/Scabrous), but single lab and Drosophila ortholog\",\n      \"pmids\": [\"23788431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EHBP1 interacts with P-Rex1 (a guanine nucleotide exchange factor implicated in invasive growth) in PTEN-expressing prostate cancer cells, and EHBP1 is essential for the anti-invasive effect of atorvastatin. EHBP1 is involved in P2X7 signaling. Notably, the EHBP1-P-Rex1 interaction was not induced by extracellular ATP (the endogenous P2X7 ligand).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, invasion assays, pharmacological inhibition\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP demonstrating interaction, siRNA knockdown with invasion phenotype, single lab\",\n      \"pmids\": [\"24451147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The molecular mechanism of EHBP1 actin-binding activation was established: (1) EHBP1's N-terminal C2 domain associates with PI(3)P, PI(5)P, and phosphatidylserine, providing membrane targeting. (2) In the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular complex with the central calponin homology (CH) domain, auto-inhibiting actin binding. (3) Binding of active Rab8 to the bMERB domain relieves this autoinhibition, freeing the CH domain to interact with actin and drive membrane tubulation. Crystal/biochemical structures of the autoinhibited CH:bMERB complex and the active bMERB:Rab8 complex were determined and validated by structure-based mutagenesis.\",\n      \"method\": \"X-ray crystallography, in vitro biochemical binding assays, structure-based mutagenesis, actin binding assays, membrane tubulation assays, lipid binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both autoinhibited and active complexes, in vitro reconstitution, structure-based mutagenesis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"32826901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila wing disc epithelium, Ehbp1 acts as a directional switch for polarized Wg/Wnt transport: AP-1 delivers Wg/Wnt basolaterally, and Ehbp1 competes with Wntless for AP-1 binding, thereby sequestering AP-1 and redirecting Wg/Wnt for apical delivery. Removing Ehbp1 coiled-coil motifs within its bMERB domain, or reducing Ehbp1 expression, leads to basolateral Wg/Wnt accumulation. This regulation of polarized Wnt delivery is conserved in vertebrates.\",\n      \"method\": \"Genetic epistasis (Drosophila), co-immunoprecipitation (AP-1 interaction), domain deletion mutants, cargo localization assays, vertebrate conservation experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis, domain deletion mutagenesis, Co-IP showing AP-1 competition, and vertebrate conservation; single lab\",\n      \"pmids\": [\"39402333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHBP1 is critically involved in dendritic arbor formation in rat hippocampal neurons. A newly identified motif specific to chordate EHBP1 proteins mediates interaction with syndapin I (an F-BAR domain protein). This function does not require the Rab GTPase-binding domain but is strictly dependent on the syndapin I binding interface and syndapin I presence. EHBP1 forms ternary complexes with syndapin I and the actin nucleator Cobl at nascent dendritic branch sites. The C2 and CH domains of EHBP1 are also required for dendritic arborization.\",\n      \"method\": \"Gain-of-function and loss-of-function in primary rat hippocampal neurons, co-immunoprecipitation, domain deletion mutants, rescue experiments, live imaging of protein dynamics at dendritic branch sites\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-specific rescue experiments, live imaging at branch sites, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38129132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ (a fibrogenic effector) in the liver. EHBP1 deficiency disrupts the intracellular localization of retromer (a complex required for sortilin stabilization), thereby increasing hepatic cholesterol accumulation and MASH fibrosis. TNF-α/PPARα pathway suppresses EHBP1 in MASH.\",\n      \"method\": \"Loss-of-function and gain-of-function mouse models, mechanistic cell biology (retromer localization, PCSK9 secretion assays, LDLR degradation assays), immunofluorescence\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss- and gain-of-function, multiple mechanistic readouts (PCSK9 secretion, LDLR, TAZ, retromer localization), multiple orthogonal methods\",\n      \"pmids\": [\"40015280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, EHBP-1 localizes to recycling endosomes and captures RAB-10-positive lipoprotein exocytic carriers through its interaction with active RAB-10, promoting delivery of exocytic cargo to recycling endosomes. The mechanism requires synergy between EHBP-1's RAB-10-binding coiled-coil domain and its PI(4,5)P2-binding C2 domain. LST-6/DENND5 was identified as the GEF for RAB-10 in this post-Golgi pathway. After EHBP-1 capture, the exocyst complex carries out subsequent trafficking steps.\",\n      \"method\": \"C. elegans and mammalian cell genetics, live imaging, domain deletion mutants, GEF identification, epistasis with exocyst complex\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging of carrier capture, domain deletion mutants, genetic epistasis with GEF and exocyst; C. elegans ortholog, single lab\",\n      \"pmids\": [\"39982707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EHBP1 localizes to the basal body and ciliary compartment of the primary cilium in human fibroblasts and RPE cells, and to the outer membrane of developing photoreceptors in retinal organoids. Dysfunction of INPP5E (due to patient mutations or CRISPR/Cas9 knockout) alters EHBP1 localization, placing EHBP1 in a ciliary functional module downstream of or regulated by INPP5E.\",\n      \"method\": \"Proximity-labeling proteomics (BioID), immunofluorescence localization in human fibroblasts/RPE, CRISPR/Cas9 knockout, patient-derived fibroblast analysis, retinal organoids\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proximity labeling identified the interaction, localization confirmed by imaging in multiple cell types, functional consequence shown via INPP5E loss-of-function; single lab\",\n      \"pmids\": [\"41805112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EHBP1 is an adaptor protein that links endosomal vesicle trafficking to the actin cytoskeleton by coupling active Rab GTPases (Rab8, Rab10) to EHD proteins and actin via its bMERB, CH, and C2 domains; its actin-binding CH domain is autoinhibited by intramolecular interaction with the bMERB domain and is activated upon Rab8 binding; EHBP1 functions in GLUT4 recycling, lipophagy, post-Golgi exocytic trafficking, Wnt polarized sorting, dendritic arborization (via a ternary complex with syndapin I and Cobl), hepatic cholesterol metabolism (through sortilin/PCSK9/LDLR pathway and retromer stabilization), and ciliary compartment organization downstream of INPP5E.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EHBP1 is a multidomain adaptor that couples endosomal membrane trafficking to the actin cytoskeleton by linking active Rab GTPases and EHD proteins to actin remodeling [#0, #2, #6]. Its N-terminal C2 domain binds phosphoinositides and phosphatidylserine to target membranes, a central calponin homology (CH) domain binds actin and drives membrane tubulation, and a C-terminal bivalent Mical/EHBP Rab-binding (bMERB) domain engages active Rab8/Rab10; in the resting state the bMERB domain folds back onto the CH domain to autoinhibit actin binding, and Rab8 binding to bMERB relieves this autoinhibition to free the CH domain for actin engagement [#6]. Through NPF-mediated binding to the EH domains of EHD1/EHD2, EHBP1 controls transferrin and GLUT4 endocytosis and is required for insulin-stimulated perinuclear GLUT4 recycling and hexose transport in adipocytes [#0, #1]. As a Rab10/Rab8 effector it captures exocytic and recycling carriers and supports cargo delivery to the plasma membrane, post-Golgi exocytic trafficking via a DENND5/LST-6-Rab10-exocyst axis, and Rab10-driven engulfment of lipid droplets during hepatic lipophagy together with EHD2 [#2, #3, #10]. EHBP1 additionally directs polarized Wnt secretion by competing with Wntless for AP-1, mediates dendritic arbor formation through a chordate-specific motif that nucleates a ternary complex with syndapin I and the actin nucleator Cobl, and regulates hepatic cholesterol handling by promoting sortilin-mediated PCSK9 secretion and stabilizing retromer localization, with its loss increasing cholesterol accumulation and MASH fibrosis [#7, #8, #9]. EHBP1 also localizes to the basal body and ciliary compartment downstream of INPP5E [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established EHBP1 as the molecular bridge connecting clathrin-mediated endocytosis to actin, answering how EHD proteins might couple vesicle traffic to the cytoskeleton.\",\n      \"evidence\": \"siRNA knockdown, domain interaction mapping and actin imaging linking EHBP1 NPF repeats to the EHD2 EH domain and a CH domain to actin\",\n      \"pmids\": [\"14676205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how actin binding is regulated\", \"Did not distinguish EHD1 vs EHD2 roles in specific cargo pathways\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a specific physiological role by showing EHBP1 and EHD1 are required for insulin-regulated GLUT4 recycling, distinguishing functional EHD partners.\",\n      \"evidence\": \"siRNA depletion, reciprocal Co-IP and glucose transport assays in adipocytes\",\n      \"pmids\": [\"15247266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the Rab GTPase driving this step\", \"Mechanism of perinuclear localization unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified EHBP1 as a direct Rab10 (and redundantly Rab8) effector, recasting it as a Rab-GTPase-linked trafficking factor.\",\n      \"evidence\": \"Yeast two-hybrid, in vivo co-localization and genetic epistasis in C. elegans\",\n      \"pmids\": [\"20573983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Rab binding unknown\", \"Did not connect Rab binding to actin regulation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended EHBP1 function to developmental signaling by showing it regulates exocytosis of the Notch modulator Scabrous.\",\n      \"evidence\": \"Drosophila loss-of-function genetics and trafficking assays\",\n      \"pmids\": [\"23788431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and ortholog\", \"Direct cargo-recognition mechanism not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked EHBP1 to P-Rex1 and anti-invasive statin action in prostate cancer, broadening its interactome.\",\n      \"evidence\": \"Co-IP, siRNA and invasion assays in PTEN-expressing prostate cancer cells\",\n      \"pmids\": [\"24451147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Functional relevance of P2X7 link unclear since interaction was ATP-independent\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed EHBP1 in lipophagy, showing Rab10 recruits EHBP1 and EHD2 to lipid droplet membranes to drive LD engulfment.\",\n      \"evidence\": \"siRNA, GTPase-defective Rab10 mutant, Co-IP and lipophagy assays in hepatocytes\",\n      \"pmids\": [\"28028537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EHBP1/EHD2 shape autophagic membranes mechanistically not resolved\", \"Connection to actin during lipophagy not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Solved the autoinhibition mechanism, explaining how Rab8 binding switches on EHBP1 actin binding and membrane tubulation.\",\n      \"evidence\": \"X-ray crystallography of autoinhibited CH:bMERB and active bMERB:Rab8 complexes with structure-based mutagenesis and in vitro assays\",\n      \"pmids\": [\"32826901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell dynamics of the switch not directly visualized\", \"Whether other partners modulate the switch unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed EHBP1 as a directional switch for polarized Wnt secretion by competing with Wntless for AP-1.\",\n      \"evidence\": \"Drosophila genetic epistasis, domain deletion, AP-1 Co-IP and vertebrate conservation\",\n      \"pmids\": [\"39402333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Quantitative basis of AP-1 competition not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a Rab-independent neuronal function in dendritic arborization through a chordate-specific syndapin I-binding motif.\",\n      \"evidence\": \"Gain/loss-of-function, domain-specific rescue, Co-IP and live imaging in rat hippocampal neurons\",\n      \"pmids\": [\"38129132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the syndapin I/Cobl ternary complex nucleates actin at branch sites not fully resolved\", \"Relationship to canonical Rab-dependent activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established EHBP1 in hepatic cholesterol metabolism via sortilin/PCSK9/LDLR and retromer stabilization, with disease relevance to MASH fibrosis.\",\n      \"evidence\": \"Mouse loss/gain-of-function and mechanistic cell biology (PCSK9 secretion, LDLR degradation, retromer localization)\",\n      \"pmids\": [\"40015280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between EHBP1 and retromer not defined\", \"How TNF-α/PPARα suppresses EHBP1 transcriptionally not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Detailed the post-Golgi exocytic mechanism in which EHBP1 captures Rab10 carriers at recycling endosomes via coiled-coil and C2 synergy, handing off to the exocyst.\",\n      \"evidence\": \"C. elegans and mammalian genetics, live imaging, domain deletion and GEF (LST-6/DENND5) identification\",\n      \"pmids\": [\"39982707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Handoff to exocyst not mechanistically reconstituted\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned EHBP1 in a ciliary module regulated by INPP5E based on basal body/ciliary localization.\",\n      \"evidence\": \"BioID proximity labeling, immunofluorescence in fibroblasts/RPE, INPP5E CRISPR knockout and patient cells, retinal organoids\",\n      \"pmids\": [\"41805112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct functional role of EHBP1 in ciliary trafficking not established\", \"Mechanism by which INPP5E controls EHBP1 localization unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EHBP1's distinct domain modules are selectively deployed across its diverse trafficking, signaling, and metabolic functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for how Rab-dependent vs Rab-independent (syndapin I) modes are partitioned across cell types\", \"Whether ciliary and hepatic roles share a common molecular mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 7, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EHD2\", \"EHD1\", \"RAB10\", \"RAB8\", \"SDPN1\", \"COBL\", \"AP-1\", \"P-Rex1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}