{"gene":"EHBP1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2003,"finding":"EHBP1 interacts with EHD2 via NPF repeats binding to EHD2's C-terminal EH domain, and together they couple clathrin-mediated endocytosis to the actin cytoskeleton; EHBP1 contains a calponin homology (CH) domain that mediates actin binding, and siRNA knockdown of EHBP1 inhibits transferrin and GLUT4 endocytosis into EEA1-positive endosomes.","method":"Co-immunoprecipitation, siRNA knockdown, transferrin/GLUT4 endocytosis assay, overexpression-induced actin reorganization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction mapping + functional knockdown with defined endocytic phenotype, foundational paper with >100 citations","pmids":["14676205"],"is_preprint":false},{"year":2004,"finding":"EHBP1 interacts with EHD1 (via EHD1's EH domain) and is required for insulin-stimulated GLUT4 recycling and glucose transport in adipocytes; siRNA depletion of EHBP1 disrupts insulin-regulated GLUT4 movements.","method":"Co-immunoprecipitation, siRNA knockdown, GLUT4 translocation assay, hexose transport assay in 3T3-L1 adipocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional siRNA knockdown with defined GLUT4 recycling phenotype, >100 citations","pmids":["15247266"],"is_preprint":false},{"year":2010,"finding":"C. elegans EHBP-1 (ortholog of EHBP1) was identified as a direct binding partner of RAB-10 in a yeast two-hybrid screen; EHBP-1 colocalizes with RAB-10 on endosomal structures and ehbp-1 loss-of-function mutants share endosome morphology and cargo localization defects with rab-10 mutants, placing EHBP1 in the RAB-10-regulated endocytic recycling pathway.","method":"Yeast two-hybrid, in vivo colocalization (GFP/RFP tagging), genetic loss-of-function in C. elegans","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus genetic epistasis and in vivo colocalization in C. elegans ortholog, >100 citations","pmids":["20573983"],"is_preprint":false},{"year":2016,"finding":"During autophagy in hepatocytes, active Rab10 recruits EHBP1 and the membrane-deforming ATPase EHD2 to nascent autophagic membranes at the lipid droplet surface; this Rab10-EHBP1-EHD2 complex is essential for LC3 recruitment to the autophagosome and for the engulfment of lipid droplets during lipophagy.","method":"siRNA knockdown, expression of GTPase-defective Rab10, immunofluorescence colocalization, lipid droplet accumulation assay in hepatocytes","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — multiple siRNA knockdowns plus dominant-negative GTPase mutant with defined lipophagy phenotype, >150 citations","pmids":["28028537"],"is_preprint":false},{"year":2013,"finding":"Drosophila EHBP1 (dEHBP1, ortholog) controls the exocytosis of Scabrous, a positive regulator of Notch signaling, during lateral inhibition to specify R8 photoreceptors; loss of dEHBP1 results in supernumerary R8 photoreceptors due to defective Scabrous trafficking.","method":"Genetic loss-of-function in Drosophila, photoreceptor fate analysis, Scabrous secretion assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with specific developmental phenotype in Drosophila ortholog, single lab","pmids":["23788431"],"is_preprint":false},{"year":2020,"finding":"EHBP1 contains an N-terminal C2 domain that binds PI(3)P, PI(5)P, and phosphatidylserine for membrane targeting; in the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular auto-inhibitory complex with the central CH domain, blocking actin binding; Rab8 binding to the bMERB domain relieves this auto-inhibition, freeing the CH domain to bind actin and drive membrane tubulation.","method":"In vitro biochemical assays, X-ray crystallography of CH:bMERB and bMERB:Rab8 complexes, structure-based mutagenesis, liposome binding assays, membrane tubulation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structures of auto-inhibited and active complexes plus mutagenesis and in vitro biochemical reconstitution","pmids":["32826901"],"is_preprint":false},{"year":2014,"finding":"EHBP1 interacts with P-Rex1 (a guanine nucleotide exchange factor implicated in invasive growth) in prostate cancer cells, and EHBP1 is required downstream of P2X7 receptor signaling for the anti-invasive effect of atorvastatin.","method":"Co-immunoprecipitation, siRNA knockdown, invasion assay in prostate cancer cells","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP for EHBP1-P-Rex1 interaction plus functional siRNA knockdown with invasion phenotype, single lab","pmids":["24451147"],"is_preprint":false},{"year":2024,"finding":"EHBP1 contains a chordata-specific motif that mediates interaction with syndapin I (an F-BAR domain membrane-shaping protein); the EHBP1–syndapin I interaction, along with the C2 and CH domains of EHBP1 and the actin nucleator Cobl, is required for dendritic arbor formation in hippocampal neurons; syndapin I organizes ternary complexes of EHBP1–syndapin I–Cobl at nascent dendritic branch sites.","method":"Co-immunoprecipitation, gain- and loss-of-function in rat primary hippocampal neurons, domain deletion/mutation analysis, live imaging of EHBP1 and syndapin I dynamics, rescue experiments","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mutagenesis, loss-of-function with specific neuromorphogenesis phenotype, rescue experiments with multiple domains","pmids":["38129132"],"is_preprint":false},{"year":2025,"finding":"EHBP1 promotes sortilin-mediated PCSK9 secretion, which leads to LDL receptor degradation, decreased LDL uptake, and reduced levels of the fibrogenic effector TAZ; EHBP1 deficiency disrupts intracellular localization of the retromer complex (required for sortilin stabilization), thereby increasing hepatic cholesterol uptake and MASH fibrosis.","method":"EHBP1 loss- and gain-of-function in mice (dietary MASH model), PCSK9 secretion assay, LDLR protein assay, retromer localization by immunofluorescence, TAZ measurement","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss- and gain-of-function with mechanistic dissection of retromer/sortilin/PCSK9/LDLR/TAZ pathway, multiple orthogonal methods","pmids":["40015280"],"is_preprint":false},{"year":2024,"finding":"In Drosophila wing disc epithelium (conserved in vertebrates), Ehbp1 acts as a directional switch for polarized Wnt/Wingless transport by competing with the Wg cargo receptor Wntless for binding to the AP-1 adaptor complex; Ehbp1 sequestration of AP-1 prevents basolateral delivery and redirects Wg for apical secretion; removal of Ehbp1's coiled-coil motifs within its bMERB domain abolishes this function.","method":"Genetic epistasis in Drosophila, co-immunoprecipitation (Ehbp1 vs. Wntless for AP-1 binding), domain deletion analysis, Wg localization assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis plus Co-IP competition assay with domain mutagenesis in Drosophila ortholog, single lab","pmids":["39402333"],"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; this mechanism requires both EHBP-1's RAB-10-binding coiled-coil domain and its PI(4,5)P2-binding C2 domain; the GEF LST-6/DENND5 specifically activates RAB-10 in this pathway, and the exocyst complex acts downstream of RAB-10-EHBP-1 capture.","method":"Genetic analysis in C. elegans, live imaging, domain deletion/mutation analysis, GEF identification by genetic epistasis, exocyst epistasis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with domain dissection in C. elegans ortholog, single lab","pmids":["39702707"],"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; INPP5E dysfunction (patient mutations or CRISPR knockout) alters EHBP1 ciliary localization, placing EHBP1 in an INPP5E-regulated ciliary functional module.","method":"Proximity-labeling proteomics (INPP5E BioID), immunofluorescence localization in fibroblasts/RPE/retinal organoids, CRISPR/Cas9 knockout of INPP5E, patient mutation fibroblasts","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — proximity proteomics plus direct localization with functional perturbation showing localization change, single lab","pmids":["41805112"],"is_preprint":false}],"current_model":"EHBP1 is an adaptor protein that links endosomal/vesicular trafficking to the actin cytoskeleton: its N-terminal C2 domain binds phosphoinositides at membranes, its central CH domain binds F-actin (auto-inhibited by intramolecular interaction with the C-terminal bMERB domain until Rab8-family GTPases bind and relieve this inhibition), its bMERB domain engages active Rab8/Rab10, and it recruits EHD1/EHD2 via NPF-EH domain interactions — together coordinating GLUT4 recycling, lipophagy, PCSK9/LDLR-mediated cholesterol metabolism, Wnt polarized secretion, neuronal dendritic arborization (via syndapin I–Cobl complexes), and ciliary function downstream of INPP5E."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of EHBP1 as an EHD2-interacting, actin-binding endocytic adaptor established its foundational role in coupling clathrin-mediated endocytosis to the actin cytoskeleton, with knockdown blocking transferrin and GLUT4 internalization.","evidence":"Co-immunoprecipitation, siRNA knockdown, and endocytosis assays in mammalian cells","pmids":["14676205"],"confidence":"High","gaps":["Structural basis for NPF–EH domain interaction not resolved","Whether EHBP1 functions beyond endocytosis was unknown","In vivo validation in animal models lacking"]},{"year":2004,"claim":"Demonstration that EHBP1 interacts with EHD1 and is required for insulin-stimulated GLUT4 recycling extended its role from endocytic internalization to regulated exocytic recycling in adipocytes.","evidence":"Co-immunoprecipitation, siRNA knockdown, GLUT4 translocation and hexose transport assays in 3T3-L1 adipocytes","pmids":["15247266"],"confidence":"High","gaps":["Whether Rab GTPases participate in this pathway was unknown","Mechanism of insulin-dependent regulation of EHBP1 not addressed"]},{"year":2010,"claim":"Discovery that the C. elegans ortholog EHBP-1 directly binds RAB-10 and shares its endosomal recycling phenotype established Rab10 as a key upstream regulator of EHBP1 function, conserved across metazoans.","evidence":"Yeast two-hybrid, in vivo colocalization, and genetic loss-of-function in C. elegans","pmids":["20573983"],"confidence":"High","gaps":["Binding interface between Rab10 and EHBP1 unresolved","Whether this interaction is direct in mammalian cells not yet tested"]},{"year":2013,"claim":"Genetic analysis in Drosophila showed that EHBP1 controls Scabrous exocytosis during photoreceptor fate determination, revealing a role in developmental signaling cargo secretion beyond constitutive recycling.","evidence":"Genetic loss-of-function in Drosophila with photoreceptor fate and Scabrous trafficking analysis","pmids":["23788431"],"confidence":"Medium","gaps":["Molecular mechanism of EHBP1 in exocytic cargo sorting not defined","Not confirmed in mammalian developmental contexts","Single laboratory study"]},{"year":2016,"claim":"Identification of a Rab10–EHBP1–EHD2 complex on autophagic membranes at lipid droplets demonstrated that EHBP1 functions in selective autophagy (lipophagy), linking it to LC3 recruitment and lipid droplet engulfment in hepatocytes.","evidence":"siRNA knockdown, dominant-negative Rab10, immunofluorescence, and lipid droplet accumulation assay in hepatocytes","pmids":["28028537"],"confidence":"High","gaps":["How EHBP1 connects to autophagosomal machinery mechanistically unclear","Whether lipophagy role extends to other cell types not tested"]},{"year":2020,"claim":"Crystal structures of the auto-inhibited CH:bMERB complex and the activating bMERB:Rab8 complex revealed the allosteric switch mechanism: Rab8 binding to the bMERB domain displaces the CH domain, enabling actin binding and membrane tubulation, providing the first structural framework for EHBP1 regulation.","evidence":"X-ray crystallography, structure-based mutagenesis, liposome binding, and membrane tubulation reconstitution in vitro","pmids":["32826901"],"confidence":"High","gaps":["Whether auto-inhibition is regulated by post-translational modifications unknown","In vivo validation of the structural switch in trafficking contexts not performed"]},{"year":2024,"claim":"Discovery that EHBP1 forms ternary complexes with syndapin I and the actin nucleator Cobl at dendritic branch sites established a neuronal-specific function for EHBP1 in dendritic arborization, mediated by a chordata-specific syndapin-binding motif.","evidence":"Co-immunoprecipitation, domain mutagenesis, loss- and gain-of-function with rescue in rat hippocampal neurons, live imaging","pmids":["38129132"],"confidence":"High","gaps":["Whether this complex is regulated by Rab GTPases is unknown","Relevance to neurodevelopmental disease not established"]},{"year":2024,"claim":"Demonstration that EHBP1 competes with Wntless for AP-1 adaptor complex binding to redirect Wnt/Wingless secretion apically revealed a new mechanism by which EHBP1 acts as a directional switch for polarized cargo sorting.","evidence":"Genetic epistasis in Drosophila, Co-IP competition assay for AP-1 binding, domain deletion analysis","pmids":["39402333"],"confidence":"Medium","gaps":["Conservation of AP-1 competition mechanism in vertebrate Wnt secretion untested","Single laboratory study","Whether bMERB coiled-coil motif mediates AP-1 binding directly or indirectly unclear"]},{"year":2025,"claim":"Mechanistic dissection in C. elegans showed that EHBP-1 captures RAB-10-positive lipoprotein exocytic carriers via its coiled-coil and C2 domains, delivering them to recycling endosomes with downstream exocyst involvement, establishing a RAB-10–EHBP-1–exocyst axis in exocytic trafficking.","evidence":"Genetic epistasis, live imaging, domain deletion and GEF identification in C. elegans","pmids":["39702707"],"confidence":"Medium","gaps":["Whether this exocytic capture mechanism is conserved in mammalian cells unknown","Direct biochemical reconstitution of the capture step not performed"]},{"year":2025,"claim":"Discovery that EHBP1 promotes sortilin-mediated PCSK9 secretion via retromer stabilization linked EHBP1 to cholesterol metabolism and MASH fibrosis; EHBP1 deficiency disrupted retromer localization, increasing hepatic LDLR levels and downstream fibrogenic TAZ signaling.","evidence":"In vivo loss- and gain-of-function in mice on MASH diet, PCSK9 secretion, LDLR, retromer localization, and TAZ assays","pmids":["40015280"],"confidence":"High","gaps":["Direct physical interaction between EHBP1 and retromer subunits not demonstrated","Whether this is Rab10-dependent in hepatocytes not addressed"]},{"year":2026,"claim":"Localization of EHBP1 to the basal body and ciliary compartment, dependent on INPP5E phosphoinositide regulation, placed EHBP1 in a ciliary functional module with potential relevance to ciliopathies.","evidence":"BioID proximity labeling, immunofluorescence in fibroblasts/RPE/retinal organoids, INPP5E knockout and patient mutations","pmids":["41805112"],"confidence":"Medium","gaps":["Functional role of EHBP1 at the cilium not established","Whether EHBP1 loss causes ciliary defects not tested","Single laboratory study"]},{"year":null,"claim":"The mechanism by which EHBP1 integrates its multiple domain-level activities (C2, CH, bMERB, NPF) to select among distinct trafficking routes — endocytic recycling, lipophagy, polarized secretion, retromer-dependent sorting, and ciliary targeting — in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model explaining pathway selectivity across cell types","Post-translational regulation of EHBP1 function unexplored","Full interactome in mammalian cells not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,9]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,7]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,3,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8]}],"complexes":["Rab10-EHBP1-EHD2 complex","EHBP1-syndapin I-Cobl complex"],"partners":["EHD1","EHD2","RAB10","RAB8A","SDPN1","COBL","PREX1","SORTILIN"],"other_free_text":[]},"mechanistic_narrative":"EHBP1 is a multidomain endosomal adaptor protein that coordinates membrane trafficking with the actin cytoskeleton across diverse cellular contexts, including endocytic recycling, lipophagy, polarized secretion, dendritic morphogenesis, cholesterol metabolism, and ciliary function. Its N-terminal C2 domain binds phosphoinositides for membrane targeting, its central calponin homology (CH) domain binds F-actin, and its C-terminal bMERB domain engages active Rab8/Rab10 GTPases; in the resting state, the bMERB domain auto-inhibits the CH domain, and Rab8 binding relieves this inhibition to enable simultaneous actin and membrane engagement [PMID:32826901]. EHBP1 recruits EHD1/EHD2 via NPF motifs to promote GLUT4 recycling and transferrin endocytosis [PMID:14676205, PMID:15247266], forms a Rab10–EHBP1–EHD2 complex required for LC3 recruitment during lipophagy [PMID:28028537], facilitates sortilin-mediated PCSK9 secretion and LDL receptor turnover through retromer complex regulation [PMID:40015280], and participates in neuronal dendritic arborization via syndapin I–Cobl complexes [PMID:38129132]. EHBP1 also directs polarized Wnt secretion by competing with Wntless for AP-1 adaptor binding [PMID:39402333] and localizes to the primary cilium in an INPP5E-dependent manner [PMID:41805112]."},"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":152,"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":133,"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":59,"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":27,"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":"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":"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":10,"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":7,"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":6,"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":"38129132","id":"PMC_38129132","title":"EHBP1 Is Critically Involved in the Dendritic Arbor Formation and Is Coupled to Factors Promoting Actin Filament Formation.","date":"2024","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38129132","citation_count":3,"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 reports","url":"https://pubmed.ncbi.nlm.nih.gov/39402333","citation_count":2,"is_preprint":false},{"pmid":"39731114","id":"PMC_39731114","title":"Association between the EHBP1 SNPs and dyslipidemia in the end-stage renal disease patients with dialysis in Chinese Han population.","date":"2024","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/39731114","citation_count":1,"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},{"pmid":"41805112","id":"PMC_41805112","title":"The EH Binding protein EHBP1 operates in a ciliary functional module affected by INPP5E dysfunction.","date":"2026","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41805112","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10515,"output_tokens":3378,"usd":0.041107},"stage2":{"model":"claude-opus-4-6","input_tokens":6738,"output_tokens":3161,"usd":0.169072},"total_usd":0.210179,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","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 binding to EHD2's C-terminal EH domain, and together they couple clathrin-mediated endocytosis to the actin cytoskeleton; EHBP1 contains a calponin homology (CH) domain that mediates actin binding, and siRNA knockdown of EHBP1 inhibits transferrin and GLUT4 endocytosis into EEA1-positive endosomes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, transferrin/GLUT4 endocytosis assay, overexpression-induced actin reorganization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction mapping + functional knockdown with defined endocytic phenotype, foundational paper with >100 citations\",\n      \"pmids\": [\"14676205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"EHBP1 interacts with EHD1 (via EHD1's EH domain) and is required for insulin-stimulated GLUT4 recycling and glucose transport in adipocytes; siRNA depletion of EHBP1 disrupts insulin-regulated GLUT4 movements.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, GLUT4 translocation assay, hexose transport assay in 3T3-L1 adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional siRNA knockdown with defined GLUT4 recycling phenotype, >100 citations\",\n      \"pmids\": [\"15247266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans EHBP-1 (ortholog of EHBP1) was identified as a direct binding partner of RAB-10 in a yeast two-hybrid screen; EHBP-1 colocalizes with RAB-10 on endosomal structures and ehbp-1 loss-of-function mutants share endosome morphology and cargo localization defects with rab-10 mutants, placing EHBP1 in the RAB-10-regulated endocytic recycling pathway.\",\n      \"method\": \"Yeast two-hybrid, in vivo colocalization (GFP/RFP tagging), genetic loss-of-function in C. elegans\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus genetic epistasis and in vivo colocalization in C. elegans ortholog, >100 citations\",\n      \"pmids\": [\"20573983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During autophagy in hepatocytes, active Rab10 recruits EHBP1 and the membrane-deforming ATPase EHD2 to nascent autophagic membranes at the lipid droplet surface; this Rab10-EHBP1-EHD2 complex is essential for LC3 recruitment to the autophagosome and for the engulfment of lipid droplets during lipophagy.\",\n      \"method\": \"siRNA knockdown, expression of GTPase-defective Rab10, immunofluorescence colocalization, lipid droplet accumulation assay in hepatocytes\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple siRNA knockdowns plus dominant-negative GTPase mutant with defined lipophagy phenotype, >150 citations\",\n      \"pmids\": [\"28028537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila EHBP1 (dEHBP1, ortholog) controls the exocytosis of Scabrous, a positive regulator of Notch signaling, during lateral inhibition to specify R8 photoreceptors; loss of dEHBP1 results in supernumerary R8 photoreceptors due to defective Scabrous trafficking.\",\n      \"method\": \"Genetic loss-of-function in Drosophila, photoreceptor fate analysis, Scabrous secretion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific developmental phenotype in Drosophila ortholog, single lab\",\n      \"pmids\": [\"23788431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EHBP1 contains an N-terminal C2 domain that binds PI(3)P, PI(5)P, and phosphatidylserine for membrane targeting; in the absence of Rab8 family members, the C-terminal bivalent Mical/EHBP Rab binding (bMERB) domain forms an intramolecular auto-inhibitory complex with the central CH domain, blocking actin binding; Rab8 binding to the bMERB domain relieves this auto-inhibition, freeing the CH domain to bind actin and drive membrane tubulation.\",\n      \"method\": \"In vitro biochemical assays, X-ray crystallography of CH:bMERB and bMERB:Rab8 complexes, structure-based mutagenesis, liposome binding assays, membrane tubulation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures of auto-inhibited and active complexes plus mutagenesis and in vitro biochemical reconstitution\",\n      \"pmids\": [\"32826901\"],\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 prostate cancer cells, and EHBP1 is required downstream of P2X7 receptor signaling for the anti-invasive effect of atorvastatin.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, invasion assay in prostate cancer cells\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP for EHBP1-P-Rex1 interaction plus functional siRNA knockdown with invasion phenotype, single lab\",\n      \"pmids\": [\"24451147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EHBP1 contains a chordata-specific motif that mediates interaction with syndapin I (an F-BAR domain membrane-shaping protein); the EHBP1–syndapin I interaction, along with the C2 and CH domains of EHBP1 and the actin nucleator Cobl, is required for dendritic arbor formation in hippocampal neurons; syndapin I organizes ternary complexes of EHBP1–syndapin I–Cobl at nascent dendritic branch sites.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function in rat primary hippocampal neurons, domain deletion/mutation analysis, live imaging of EHBP1 and syndapin I dynamics, rescue experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mutagenesis, loss-of-function with specific neuromorphogenesis phenotype, rescue experiments with multiple domains\",\n      \"pmids\": [\"38129132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EHBP1 promotes sortilin-mediated PCSK9 secretion, which leads to LDL receptor degradation, decreased LDL uptake, and reduced levels of the fibrogenic effector TAZ; EHBP1 deficiency disrupts intracellular localization of the retromer complex (required for sortilin stabilization), thereby increasing hepatic cholesterol uptake and MASH fibrosis.\",\n      \"method\": \"EHBP1 loss- and gain-of-function in mice (dietary MASH model), PCSK9 secretion assay, LDLR protein assay, retromer localization by immunofluorescence, TAZ measurement\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss- and gain-of-function with mechanistic dissection of retromer/sortilin/PCSK9/LDLR/TAZ pathway, multiple orthogonal methods\",\n      \"pmids\": [\"40015280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila wing disc epithelium (conserved in vertebrates), Ehbp1 acts as a directional switch for polarized Wnt/Wingless transport by competing with the Wg cargo receptor Wntless for binding to the AP-1 adaptor complex; Ehbp1 sequestration of AP-1 prevents basolateral delivery and redirects Wg for apical secretion; removal of Ehbp1's coiled-coil motifs within its bMERB domain abolishes this function.\",\n      \"method\": \"Genetic epistasis in Drosophila, co-immunoprecipitation (Ehbp1 vs. Wntless for AP-1 binding), domain deletion analysis, Wg localization assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus Co-IP competition assay with domain mutagenesis in Drosophila ortholog, single lab\",\n      \"pmids\": [\"39402333\"],\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; this mechanism requires both EHBP-1's RAB-10-binding coiled-coil domain and its PI(4,5)P2-binding C2 domain; the GEF LST-6/DENND5 specifically activates RAB-10 in this pathway, and the exocyst complex acts downstream of RAB-10-EHBP-1 capture.\",\n      \"method\": \"Genetic analysis in C. elegans, live imaging, domain deletion/mutation analysis, GEF identification by genetic epistasis, exocyst epistasis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with domain dissection in C. elegans ortholog, single lab\",\n      \"pmids\": [\"39702707\"],\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; INPP5E dysfunction (patient mutations or CRISPR knockout) alters EHBP1 ciliary localization, placing EHBP1 in an INPP5E-regulated ciliary functional module.\",\n      \"method\": \"Proximity-labeling proteomics (INPP5E BioID), immunofluorescence localization in fibroblasts/RPE/retinal organoids, CRISPR/Cas9 knockout of INPP5E, patient mutation fibroblasts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity proteomics plus direct localization with functional perturbation showing localization change, single lab\",\n      \"pmids\": [\"41805112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EHBP1 is an adaptor protein that links endosomal/vesicular trafficking to the actin cytoskeleton: its N-terminal C2 domain binds phosphoinositides at membranes, its central CH domain binds F-actin (auto-inhibited by intramolecular interaction with the C-terminal bMERB domain until Rab8-family GTPases bind and relieve this inhibition), its bMERB domain engages active Rab8/Rab10, and it recruits EHD1/EHD2 via NPF-EH domain interactions — together coordinating GLUT4 recycling, lipophagy, PCSK9/LDLR-mediated cholesterol metabolism, Wnt polarized secretion, neuronal dendritic arborization (via syndapin I–Cobl complexes), and ciliary function downstream of INPP5E.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EHBP1 is a multidomain endosomal adaptor protein that coordinates membrane trafficking with the actin cytoskeleton across diverse cellular contexts, including endocytic recycling, lipophagy, polarized secretion, dendritic morphogenesis, cholesterol metabolism, and ciliary function. Its N-terminal C2 domain binds phosphoinositides for membrane targeting, its central calponin homology (CH) domain binds F-actin, and its C-terminal bMERB domain engages active Rab8/Rab10 GTPases; in the resting state, the bMERB domain auto-inhibits the CH domain, and Rab8 binding relieves this inhibition to enable simultaneous actin and membrane engagement [PMID:32826901]. EHBP1 recruits EHD1/EHD2 via NPF motifs to promote GLUT4 recycling and transferrin endocytosis [PMID:14676205, PMID:15247266], forms a Rab10–EHBP1–EHD2 complex required for LC3 recruitment during lipophagy [PMID:28028537], facilitates sortilin-mediated PCSK9 secretion and LDL receptor turnover through retromer complex regulation [PMID:40015280], and participates in neuronal dendritic arborization via syndapin I–Cobl complexes [PMID:38129132]. EHBP1 also directs polarized Wnt secretion by competing with Wntless for AP-1 adaptor binding [PMID:39402333] and localizes to the primary cilium in an INPP5E-dependent manner [PMID:41805112].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of EHBP1 as an EHD2-interacting, actin-binding endocytic adaptor established its foundational role in coupling clathrin-mediated endocytosis to the actin cytoskeleton, with knockdown blocking transferrin and GLUT4 internalization.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and endocytosis assays in mammalian cells\",\n      \"pmids\": [\"14676205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for NPF–EH domain interaction not resolved\", \"Whether EHBP1 functions beyond endocytosis was unknown\", \"In vivo validation in animal models lacking\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that EHBP1 interacts with EHD1 and is required for insulin-stimulated GLUT4 recycling extended its role from endocytic internalization to regulated exocytic recycling in adipocytes.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, GLUT4 translocation and hexose transport assays in 3T3-L1 adipocytes\",\n      \"pmids\": [\"15247266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab GTPases participate in this pathway was unknown\", \"Mechanism of insulin-dependent regulation of EHBP1 not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that the C. elegans ortholog EHBP-1 directly binds RAB-10 and shares its endosomal recycling phenotype established Rab10 as a key upstream regulator of EHBP1 function, conserved across metazoans.\",\n      \"evidence\": \"Yeast two-hybrid, in vivo colocalization, and genetic loss-of-function in C. elegans\",\n      \"pmids\": [\"20573983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface between Rab10 and EHBP1 unresolved\", \"Whether this interaction is direct in mammalian cells not yet tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic analysis in Drosophila showed that EHBP1 controls Scabrous exocytosis during photoreceptor fate determination, revealing a role in developmental signaling cargo secretion beyond constitutive recycling.\",\n      \"evidence\": \"Genetic loss-of-function in Drosophila with photoreceptor fate and Scabrous trafficking analysis\",\n      \"pmids\": [\"23788431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of EHBP1 in exocytic cargo sorting not defined\", \"Not confirmed in mammalian developmental contexts\", \"Single laboratory study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of a Rab10–EHBP1–EHD2 complex on autophagic membranes at lipid droplets demonstrated that EHBP1 functions in selective autophagy (lipophagy), linking it to LC3 recruitment and lipid droplet engulfment in hepatocytes.\",\n      \"evidence\": \"siRNA knockdown, dominant-negative Rab10, immunofluorescence, and lipid droplet accumulation assay in hepatocytes\",\n      \"pmids\": [\"28028537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EHBP1 connects to autophagosomal machinery mechanistically unclear\", \"Whether lipophagy role extends to other cell types not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Crystal structures of the auto-inhibited CH:bMERB complex and the activating bMERB:Rab8 complex revealed the allosteric switch mechanism: Rab8 binding to the bMERB domain displaces the CH domain, enabling actin binding and membrane tubulation, providing the first structural framework for EHBP1 regulation.\",\n      \"evidence\": \"X-ray crystallography, structure-based mutagenesis, liposome binding, and membrane tubulation reconstitution in vitro\",\n      \"pmids\": [\"32826901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether auto-inhibition is regulated by post-translational modifications unknown\", \"In vivo validation of the structural switch in trafficking contexts not performed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that EHBP1 forms ternary complexes with syndapin I and the actin nucleator Cobl at dendritic branch sites established a neuronal-specific function for EHBP1 in dendritic arborization, mediated by a chordata-specific syndapin-binding motif.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mutagenesis, loss- and gain-of-function with rescue in rat hippocampal neurons, live imaging\",\n      \"pmids\": [\"38129132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this complex is regulated by Rab GTPases is unknown\", \"Relevance to neurodevelopmental disease not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that EHBP1 competes with Wntless for AP-1 adaptor complex binding to redirect Wnt/Wingless secretion apically revealed a new mechanism by which EHBP1 acts as a directional switch for polarized cargo sorting.\",\n      \"evidence\": \"Genetic epistasis in Drosophila, Co-IP competition assay for AP-1 binding, domain deletion analysis\",\n      \"pmids\": [\"39402333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of AP-1 competition mechanism in vertebrate Wnt secretion untested\", \"Single laboratory study\", \"Whether bMERB coiled-coil motif mediates AP-1 binding directly or indirectly unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistic dissection in C. elegans showed that EHBP-1 captures RAB-10-positive lipoprotein exocytic carriers via its coiled-coil and C2 domains, delivering them to recycling endosomes with downstream exocyst involvement, establishing a RAB-10–EHBP-1–exocyst axis in exocytic trafficking.\",\n      \"evidence\": \"Genetic epistasis, live imaging, domain deletion and GEF identification in C. elegans\",\n      \"pmids\": [\"39702707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this exocytic capture mechanism is conserved in mammalian cells unknown\", \"Direct biochemical reconstitution of the capture step not performed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that EHBP1 promotes sortilin-mediated PCSK9 secretion via retromer stabilization linked EHBP1 to cholesterol metabolism and MASH fibrosis; EHBP1 deficiency disrupted retromer localization, increasing hepatic LDLR levels and downstream fibrogenic TAZ signaling.\",\n      \"evidence\": \"In vivo loss- and gain-of-function in mice on MASH diet, PCSK9 secretion, LDLR, retromer localization, and TAZ assays\",\n      \"pmids\": [\"40015280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between EHBP1 and retromer subunits not demonstrated\", \"Whether this is Rab10-dependent in hepatocytes not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Localization of EHBP1 to the basal body and ciliary compartment, dependent on INPP5E phosphoinositide regulation, placed EHBP1 in a ciliary functional module with potential relevance to ciliopathies.\",\n      \"evidence\": \"BioID proximity labeling, immunofluorescence in fibroblasts/RPE/retinal organoids, INPP5E knockout and patient mutations\",\n      \"pmids\": [\"41805112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of EHBP1 at the cilium not established\", \"Whether EHBP1 loss causes ciliary defects not tested\", \"Single laboratory study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which EHBP1 integrates its multiple domain-level activities (C2, CH, bMERB, NPF) to select among distinct trafficking routes — endocytic recycling, lipophagy, polarized secretion, retromer-dependent sorting, and ciliary targeting — in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model explaining pathway selectivity across cell types\", \"Post-translational regulation of EHBP1 function unexplored\", \"Full interactome in mammalian cells not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 3, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"Rab10-EHBP1-EHD2 complex\",\n      \"EHBP1-syndapin I-Cobl complex\"\n    ],\n    \"partners\": [\n      \"EHD1\",\n      \"EHD2\",\n      \"RAB10\",\n      \"RAB8A\",\n      \"SDPN1\",\n      \"COBL\",\n      \"PREX1\",\n      \"SORTILIN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}