{"gene":"SH3BP1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2011,"finding":"SH3BP1 is a RhoGAP that physically associates with the exocyst complex and localizes to the leading edge of motile cells, where its GAP activity on Rac1 is required for normal cell migration; loss of SH3BP1 causes abnormally high Rac1 activity at the cell front, disorganized protrusions, and slow migration.","method":"Co-immunoprecipitation of SH3BP1 with exocyst components, RNAi knockdown with in vivo FRET-based Rac1 biosensors and cell morphodynamics analysis, rescue with constitutively active Rac1","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, live biosensor imaging, loss-of-function rescue, multiple orthogonal methods in a single focused study","pmids":["21658605"],"is_preprint":false},{"year":2012,"finding":"SH3BP1 acts as a GAP for Cdc42 (and Rac) at forming epithelial cell-cell junctions; it forms a complex with JACOP/paracingulin and CD2AP (junctional adaptors) and the actin-capping protein CapZ; this complex is recruited to sites of active membrane remodeling where it confines Cdc42 activity spatially and temporally to enable junction assembly and epithelial morphogenesis.","method":"siRNA functional screen, co-immunoprecipitation of the SH3BP1/JACOP/CD2AP/CapZ complex, Cdc42 activity assays, live imaging of junction formation upon SH3BP1 depletion","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying multi-protein complex, functional siRNA screen with defined phenotype (filopodia, stalled membrane remodeling), Cdc42 activity assays; single lab but multiple orthogonal methods","pmids":["22891260"],"is_preprint":false},{"year":2015,"finding":"SH3BP1 (along with ARHGAP12 and ARHGAP25) is recruited to large phagocytic cups by PI3K-generated PtdIns(3,4,5)P3 and is responsible for inactivating Rac and Cdc42 at the cup; silencing these GAPs impairs phagocytosis of large but not small targets, demonstrating that PI3K-dependent GAP recruitment and GTPase inactivation are essential to complete large-particle internalization.","method":"RhoGAP family siRNA screen (62 members), selective knockdown with phagocytosis assays measuring large vs. small particle uptake, live imaging of GAP recruitment and PIP3 distribution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale RNAi screen with functional phagocytosis readout, live imaging of subcellular recruitment, PI3K inhibitor epistasis; replicated across three GAPs in a single rigorous study","pmids":["26465210"],"is_preprint":false},{"year":2014,"finding":"SH3BP1 mediates Semaphorin 3E (Sema3E)-induced cell collapse downstream of PlexinD1 by interacting physically with PlexinD1 and reducing Rac1 activity; it was identified as a key downstream effector in a genome-wide RNAi screen for Sema3E-PlexinD1 signaling.","method":"Image-based genome-wide RNAi screen, co-immunoprecipitation of SH3BP1 with PlexinD1, Rac1 activity assays upon SH3BP1 knockdown","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide functional screen plus Co-IP with PlexinD1 and Rac1 activity measurement; single lab, moderate validation depth","pmids":["24841563"],"is_preprint":false},{"year":2018,"finding":"SH3BP1 (together with RICH1) acts as a GAP that locally deactivates membrane-bound, GTP-loaded Cdc42 at sites pre-primed for fast endophilin-mediated endocytosis (FEME), generating the transient assembly and disassembly of endophilin spots that last 5–10 seconds.","method":"Colocalization of 65 BAR-domain proteins with endophilin spots, live imaging of Cdc42 activity at FEME sites, genetic knockdown of RICH1 and SH3BP1 with FEME phenotype readout","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic BAR-domain screen, live imaging, loss-of-function; single lab and abstract-level detail limits full confidence","pmids":["30061681"],"is_preprint":false},{"year":2012,"finding":"BGIN, a brain-specific splice variant that incorporates exons from the SH3BP1 locus (BAR and GAP domains) fused to a partial CIN phosphatase domain, uses its poly-ubiquitin-binding module to localize to membranes and detergent-insoluble fractions, where it inactivates a membranous Rac1 population and consequently suppresses Nox1-dependent ROS generation.","method":"Characterization of splice variant by mass spectrometry (Yates lab), subcellular fractionation, poly-Ub binding assays, Rac1 activity assays, ROS measurement, colocalization in AD brain tissue","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays (fractionation, binding, activity, ROS), MS-confirmed splice variant; single lab, no structural validation","pmids":["23223568"],"is_preprint":false},{"year":2022,"finding":"PACSIN2 directly binds and inhibits SH3BP1; Cobll1 competes for PACSIN2 binding with higher affinity, releasing SH3BP1 to activate downstream Rac1 signaling; this Cobll1/PACSIN2/SH3BP1 pathway promotes TKI resistance and blast crisis progression in CML.","method":"Co-immunoprecipitation demonstrating PACSIN2–SH3BP1 and Cobll1–PACSIN2 interactions, competitive binding assays, Rac1 activity assays, siRNA knockdown with apoptosis and resistance readouts","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, competitive binding, functional knockdown with pathway readout; single lab","pmids":["35352878"],"is_preprint":false},{"year":2017,"finding":"SH3BP1 is a direct transcriptional target of the Hippo pathway effector TAZ in prostate cancer cells, mediating TAZ's pro-migratory function; knockdown of SH3BP1 partially reverses the migration-promoting effect of TAZ overexpression.","method":"Luciferase reporter and ChIP assays establishing SH3BP1 as a direct TAZ target gene, siRNA knockdown of SH3BP1 in TAZ-overexpressing cells with migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional target validation with ChIP and reporter assays plus functional rescue; single lab","pmids":["28408625"],"is_preprint":false},{"year":2025,"finding":"SH3BP1 is required for primary granule release (degranulation) in neutrophils; its promoter region is bound by HDAC2, which represses SH3BP1 expression, and HDAC2 inhibition upregulates SH3BP1; knockdown of SH3BP1 in HL-60 cells impairs primary granule release in vitro.","method":"Microarray and ChIP-seq in patient neutrophils, siRNA knockdown in HL-60 cells with granule release assays, HDAC2 inhibitor treatment with expression and degranulation readouts","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq establishing HDAC2 binding, loss-of-function with functional granule release readout; single lab, limited mechanistic depth on SH3BP1 itself","pmids":["39832064"],"is_preprint":false}],"current_model":"SH3BP1 is a BAR domain-containing RhoGAP that inactivates Rac1 and Cdc42 at specific subcellular locations—the leading edge of migrating cells (via the exocyst complex), forming epithelial junctions (via a JACOP/CD2AP/CapZ scaffold), large phagocytic cups (recruited by PI3K-generated PIP3), and FEME endocytic sites (with RICH1)—to spatiotemporally control actin dynamics, membrane remodeling, and vesicle trafficking; its activity is regulated by the PACSIN2/Cobll1 axis and its transcription is directly driven by TAZ and repressed by HDAC2."},"narrative":{"mechanistic_narrative":"SH3BP1 is a BAR domain-containing RhoGAP that spatiotemporally restricts the activity of the small GTPases Rac1 and Cdc42 at discrete membrane sites to coordinate actin dynamics, membrane remodeling, and vesicle trafficking [PMID:21658605, PMID:22891260]. At the leading edge of migrating cells it physically associates with the exocyst complex and inactivates Rac1 to organize protrusions and sustain normal migration; its loss elevates front-edge Rac1 activity and slows motility [PMID:21658605]. At forming epithelial cell-cell junctions it assembles with the adaptors JACOP/paracingulin and CD2AP and the actin-capping protein CapZ to confine Cdc42 activity and enable junction assembly [PMID:22891260]. The same GAP activity is deployed during large-particle phagocytosis, where PI3K-generated PtdIns(3,4,5)P3 recruits SH3BP1 to the phagocytic cup to inactivate Rac and Cdc42 [PMID:26465210], and at fast endophilin-mediated endocytosis sites, where SH3BP1 together with RICH1 locally deactivates GTP-loaded Cdc42 to drive the transient cycling of endophilin spots [PMID:30061681]. SH3BP1 also operates downstream of Sema3E–PlexinD1 signaling, binding PlexinD1 and lowering Rac1 activity to mediate cell collapse [PMID:24841563]. Its activity is gated by PACSIN2, which binds and inhibits SH3BP1 until Cobll1 competitively displaces PACSIN2 to release Rac1 signaling [PMID:35352878], while its transcription is directly driven by the Hippo effector TAZ [PMID:28408625] and repressed by HDAC2 [PMID:39832064].","teleology":[{"year":2011,"claim":"Established SH3BP1 as a RhoGAP that links the exocyst to localized Rac1 inactivation, answering how cells spatially confine GTPase activity at the migrating front.","evidence":"Co-IP with exocyst components, FRET-based Rac1 biosensors, RNAi knockdown with rescue by constitutively active Rac1","pmids":["21658605"],"confidence":"High","gaps":["Structural basis of exocyst association not resolved","Whether Cdc42 is also a target at the leading edge not addressed"]},{"year":2012,"claim":"Showed SH3BP1 confines Cdc42 activity at nascent epithelial junctions through a defined adaptor/capping-protein scaffold, extending its GAP role to junction assembly and morphogenesis.","evidence":"siRNA functional screen, reciprocal Co-IP of the SH3BP1/JACOP/CD2AP/CapZ complex, Cdc42 activity assays, live junction imaging","pmids":["22891260"],"confidence":"High","gaps":["How the scaffold is recruited to remodeling sites not defined","Direct binding topology within the complex not mapped"]},{"year":2012,"claim":"Characterized a brain-specific splice variant (BGIN) fusing SH3BP1 BAR/GAP domains to a partial phosphatase domain, linking membrane-targeted Rac1 inactivation to suppression of Nox1-dependent ROS.","evidence":"MS-confirmed splice variant, subcellular fractionation, poly-Ub binding assays, Rac1 activity and ROS measurements, colocalization in AD brain tissue","pmids":["23223568"],"confidence":"Medium","gaps":["No structural validation of the fusion product","Physiological prevalence and function of BGIN in normal brain unclear"]},{"year":2014,"claim":"Placed SH3BP1 downstream of Sema3E–PlexinD1 as a Rac1-suppressing effector mediating cell collapse, connecting it to guidance receptor signaling.","evidence":"Genome-wide image-based RNAi screen, Co-IP with PlexinD1, Rac1 activity assays upon knockdown","pmids":["24841563"],"confidence":"Medium","gaps":["Direct vs. indirect PlexinD1 binding not distinguished","In vivo relevance to axon guidance not tested"]},{"year":2015,"claim":"Demonstrated that PI3K-generated PIP3 recruits SH3BP1 to large phagocytic cups to inactivate Rac and Cdc42, explaining the size-selective requirement for GAP activity in phagocytosis.","evidence":"RhoGAP family siRNA screen, large vs. small particle phagocytosis assays, live imaging of GAP and PIP3 distribution, PI3K inhibitor epistasis","pmids":["26465210"],"confidence":"High","gaps":["Whether SH3BP1 binds PIP3 directly or via partners not resolved","Redundancy with ARHGAP12/ARHGAP25 not fully dissected"]},{"year":2017,"claim":"Identified SH3BP1 as a direct transcriptional target of TAZ, providing a transcriptional route by which Hippo signaling drives migration.","evidence":"Luciferase reporter and ChIP assays, siRNA knockdown in TAZ-overexpressing prostate cancer cells with migration assays","pmids":["28408625"],"confidence":"Medium","gaps":["Link to GAP catalytic activity in this context not shown","Generality beyond prostate cancer cells untested"]},{"year":2018,"claim":"Showed SH3BP1 with RICH1 locally deactivates Cdc42 at FEME sites, tying the GAP to the rapid assembly/disassembly cycling of endophilin spots.","evidence":"Colocalization screen of 65 BAR-domain proteins, live imaging of Cdc42 activity at FEME sites, RICH1/SH3BP1 knockdown with FEME readout","pmids":["30061681"],"confidence":"Medium","gaps":["Functional relationship between SH3BP1 and RICH1 not biochemically defined","Abstract-level mechanistic detail limits depth"]},{"year":2022,"claim":"Defined an upstream regulatory switch in which PACSIN2 binds and inhibits SH3BP1 until Cobll1 competitively displaces it, controlling Rac1 signaling and CML therapy resistance.","evidence":"Reciprocal Co-IP, competitive binding assays, Rac1 activity assays, siRNA knockdown with apoptosis/resistance readouts","pmids":["35352878"],"confidence":"Medium","gaps":["Structural basis of competitive binding not resolved","Whether inhibition acts on GAP catalysis or localization unclear"]},{"year":2025,"claim":"Linked SH3BP1 to neutrophil primary granule release and showed its expression is repressed by promoter-bound HDAC2, extending its role to immune cell degranulation.","evidence":"Microarray and ChIP-seq in patient neutrophils, siRNA knockdown in HL-60 cells with granule release assays, HDAC2 inhibitor treatment","pmids":["39832064"],"confidence":"Medium","gaps":["Mechanistic role of SH3BP1 GAP activity in degranulation not defined","Whether granule effect is GTPase-dependent untested"]},{"year":null,"claim":"How SH3BP1 is selectively targeted to distinct membrane compartments and whether a single structural mechanism integrates its BAR-domain membrane binding with substrate (Rac1 vs. Cdc42) choice remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SH3BP1 BAR/GAP architecture in the corpus","Determinants of Rac1 vs. Cdc42 selectivity across sites undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8]}],"complexes":["exocyst","SH3BP1/JACOP/CD2AP/CapZ junctional complex"],"partners":["EXOC (EXOCYST)","CGN/JACOP","CD2AP","CAPZ","PLXND1","RICH1","PACSIN2","COBLL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3L3","full_name":"SH3 domain-binding protein 1","aliases":[],"length_aa":701,"mass_kda":75.7,"function":"GTPase activating protein (GAP) which specifically converts GTP-bound Rho-type GTPases including RAC1 and CDC42 in their inactive GDP-bound form. By specifically inactivating RAC1 at the leading edge of migrating cells, it regulates the spatiotemporal organization of cell protrusions which is important for proper cell migration (PubMed:21658605). Also negatively regulates CDC42 in the process of actin remodeling and the formation of epithelial cell junctions (PubMed:22891260). Through its GAP activity toward RAC1 and/or CDC42 plays a specific role in phagocytosis of large particles. Specifically recruited by a PI3 kinase/PI3K-dependent mechanism to sites of large particles engagement, inactivates RAC1 and/or CDC42 allowing the reorganization of the underlying actin cytoskeleton required for engulfment (PubMed:26465210). It also plays a role in angiogenesis and the process of repulsive guidance as part of a semaphorin-plexin signaling pathway. Following the binding of PLXND1 to extracellular SEMA3E it dissociates from PLXND1 and inactivates RAC1, inducing the intracellular reorganization of the actin cytoskeleton and the collapse of cells (PubMed:24841563)","subcellular_location":"Cell projection; Cell junction, tight junction; Cell junction, adherens junction; Cell projection, phagocytic cup; Nucleus; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q9Y3L3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3BP1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARHGAP17","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SH3BP1","total_profiled":1310},"omim":[{"mim_id":"617716","title":"RHO GTPase-ACTIVATING PROTEIN 44; ARHGAP44","url":"https://www.omim.org/entry/617716"},{"mim_id":"617368","title":"SH3 DOMAIN-BINDING PROTEIN 1; SH3BP1","url":"https://www.omim.org/entry/617368"},{"mim_id":"609246","title":"PYRIDOXAL PHOSPHATASE; PDXP","url":"https://www.omim.org/entry/609246"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":38.9}],"url":"https://www.proteinatlas.org/search/SH3BP1"},"hgnc":{"alias_symbol":["ARHGAP43"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3L3","domains":[{"cath_id":"1.10.555.10","chopping":"287-435_446-467","consensus_level":"high","plddt":91.3376,"start":287,"end":467}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3L3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3L3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3L3-F1-predicted_aligned_error_v6.png","plddt_mean":70.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3BP1","jax_strain_url":"https://www.jax.org/strain/search?query=SH3BP1"},"sequence":{"accession":"Q9Y3L3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3L3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3L3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3L3"}},"corpus_meta":[{"pmid":"26465210","id":"PMC_26465210","title":"Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26465210","citation_count":173,"is_preprint":false},{"pmid":"25483301","id":"PMC_25483301","title":"Epithelial junctions and Rho family GTPases: the zonular signalosome.","date":"2014","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/25483301","citation_count":146,"is_preprint":false},{"pmid":"25469537","id":"PMC_25469537","title":"The interdependence of the Rho GTPases and apicobasal cell polarity.","date":"2014","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/25469537","citation_count":98,"is_preprint":false},{"pmid":"30061681","id":"PMC_30061681","title":"FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis.","date":"2018","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30061681","citation_count":78,"is_preprint":false},{"pmid":"21658605","id":"PMC_21658605","title":"SH3BP1, an exocyst-associated RhoGAP, inactivates Rac1 at the front to drive cell motility.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21658605","citation_count":67,"is_preprint":false},{"pmid":"22891260","id":"PMC_22891260","title":"Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22891260","citation_count":66,"is_preprint":false},{"pmid":"28408625","id":"PMC_28408625","title":"ETS (E26 transformation-specific) up-regulation of the transcriptional co-activator TAZ promotes cell migration and metastasis in prostate cancer.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28408625","citation_count":46,"is_preprint":false},{"pmid":"28498728","id":"PMC_28498728","title":"A family affair: A Ral-exocyst-centered network links Ras, Rac, Rho signaling to control cell migration.","date":"2017","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/28498728","citation_count":32,"is_preprint":false},{"pmid":"24841563","id":"PMC_24841563","title":"An image-based RNAi screen identifies SH3BP1 as a key effector of Semaphorin 3E-PlexinD1 signaling.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24841563","citation_count":25,"is_preprint":false},{"pmid":"28786507","id":"PMC_28786507","title":"SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28786507","citation_count":24,"is_preprint":false},{"pmid":"32378260","id":"PMC_32378260","title":"Comprehensive analysis on the whole Rho-GAP family reveals that ARHGAP4 suppresses EMT in epithelial cells under negative regulation by Septin9.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32378260","citation_count":24,"is_preprint":false},{"pmid":"26933917","id":"PMC_26933917","title":"SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26933917","citation_count":23,"is_preprint":false},{"pmid":"23223568","id":"PMC_23223568","title":"A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23223568","citation_count":15,"is_preprint":false},{"pmid":"35238118","id":"PMC_35238118","title":"Development and validation of an RNA sequencing panel for gene fusions in soft tissue sarcoma.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35238118","citation_count":13,"is_preprint":false},{"pmid":"35352878","id":"PMC_35352878","title":"Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35352878","citation_count":7,"is_preprint":false},{"pmid":"35110962","id":"PMC_35110962","title":"Screening of Important Markers in Peripheral Blood Mononuclear Cells to Predict Female Osteoporosis Risk Using LASSO Regression Algorithm and SVM Method.","date":"2022","source":"Evolutionary bioinformatics 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Zuchtungsbiologie","url":"https://pubmed.ncbi.nlm.nih.gov/37807719","citation_count":3,"is_preprint":false},{"pmid":"37114076","id":"PMC_37114076","title":"SH3BP1 Regulates Melanoma Progression Through Race1/Wace2 Signaling Pathway.","date":"2023","source":"Clinical Medicine Insights. 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loss of SH3BP1 causes abnormally high Rac1 activity at the cell front, disorganized protrusions, and slow migration.\",\n      \"method\": \"Co-immunoprecipitation of SH3BP1 with exocyst components, RNAi knockdown with in vivo FRET-based Rac1 biosensors and cell morphodynamics analysis, rescue with constitutively active Rac1\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, live biosensor imaging, loss-of-function rescue, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"21658605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SH3BP1 acts as a GAP for Cdc42 (and Rac) at forming epithelial cell-cell junctions; it forms a complex with JACOP/paracingulin and CD2AP (junctional adaptors) and the actin-capping protein CapZ; this complex is recruited to sites of active membrane remodeling where it confines Cdc42 activity spatially and temporally to enable junction assembly and epithelial morphogenesis.\",\n      \"method\": \"siRNA functional screen, co-immunoprecipitation of the SH3BP1/JACOP/CD2AP/CapZ complex, Cdc42 activity assays, live imaging of junction formation upon SH3BP1 depletion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying multi-protein complex, functional siRNA screen with defined phenotype (filopodia, stalled membrane remodeling), Cdc42 activity assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22891260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SH3BP1 (along with ARHGAP12 and ARHGAP25) is recruited to large phagocytic cups by PI3K-generated PtdIns(3,4,5)P3 and is responsible for inactivating Rac and Cdc42 at the cup; silencing these GAPs impairs phagocytosis of large but not small targets, demonstrating that PI3K-dependent GAP recruitment and GTPase inactivation are essential to complete large-particle internalization.\",\n      \"method\": \"RhoGAP family siRNA screen (62 members), selective knockdown with phagocytosis assays measuring large vs. small particle uptake, live imaging of GAP recruitment and PIP3 distribution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale RNAi screen with functional phagocytosis readout, live imaging of subcellular recruitment, PI3K inhibitor epistasis; replicated across three GAPs in a single rigorous study\",\n      \"pmids\": [\"26465210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SH3BP1 mediates Semaphorin 3E (Sema3E)-induced cell collapse downstream of PlexinD1 by interacting physically with PlexinD1 and reducing Rac1 activity; it was identified as a key downstream effector in a genome-wide RNAi screen for Sema3E-PlexinD1 signaling.\",\n      \"method\": \"Image-based genome-wide RNAi screen, co-immunoprecipitation of SH3BP1 with PlexinD1, Rac1 activity assays upon SH3BP1 knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide functional screen plus Co-IP with PlexinD1 and Rac1 activity measurement; single lab, moderate validation depth\",\n      \"pmids\": [\"24841563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SH3BP1 (together with RICH1) acts as a GAP that locally deactivates membrane-bound, GTP-loaded Cdc42 at sites pre-primed for fast endophilin-mediated endocytosis (FEME), generating the transient assembly and disassembly of endophilin spots that last 5–10 seconds.\",\n      \"method\": \"Colocalization of 65 BAR-domain proteins with endophilin spots, live imaging of Cdc42 activity at FEME sites, genetic knockdown of RICH1 and SH3BP1 with FEME phenotype readout\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic BAR-domain screen, live imaging, loss-of-function; single lab and abstract-level detail limits full confidence\",\n      \"pmids\": [\"30061681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BGIN, a brain-specific splice variant that incorporates exons from the SH3BP1 locus (BAR and GAP domains) fused to a partial CIN phosphatase domain, uses its poly-ubiquitin-binding module to localize to membranes and detergent-insoluble fractions, where it inactivates a membranous Rac1 population and consequently suppresses Nox1-dependent ROS generation.\",\n      \"method\": \"Characterization of splice variant by mass spectrometry (Yates lab), subcellular fractionation, poly-Ub binding assays, Rac1 activity assays, ROS measurement, colocalization in AD brain tissue\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays (fractionation, binding, activity, ROS), MS-confirmed splice variant; single lab, no structural validation\",\n      \"pmids\": [\"23223568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PACSIN2 directly binds and inhibits SH3BP1; Cobll1 competes for PACSIN2 binding with higher affinity, releasing SH3BP1 to activate downstream Rac1 signaling; this Cobll1/PACSIN2/SH3BP1 pathway promotes TKI resistance and blast crisis progression in CML.\",\n      \"method\": \"Co-immunoprecipitation demonstrating PACSIN2–SH3BP1 and Cobll1–PACSIN2 interactions, competitive binding assays, Rac1 activity assays, siRNA knockdown with apoptosis and resistance readouts\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, competitive binding, functional knockdown with pathway readout; single lab\",\n      \"pmids\": [\"35352878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3BP1 is a direct transcriptional target of the Hippo pathway effector TAZ in prostate cancer cells, mediating TAZ's pro-migratory function; knockdown of SH3BP1 partially reverses the migration-promoting effect of TAZ overexpression.\",\n      \"method\": \"Luciferase reporter and ChIP assays establishing SH3BP1 as a direct TAZ target gene, siRNA knockdown of SH3BP1 in TAZ-overexpressing cells with migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional target validation with ChIP and reporter assays plus functional rescue; single lab\",\n      \"pmids\": [\"28408625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SH3BP1 is required for primary granule release (degranulation) in neutrophils; its promoter region is bound by HDAC2, which represses SH3BP1 expression, and HDAC2 inhibition upregulates SH3BP1; knockdown of SH3BP1 in HL-60 cells impairs primary granule release in vitro.\",\n      \"method\": \"Microarray and ChIP-seq in patient neutrophils, siRNA knockdown in HL-60 cells with granule release assays, HDAC2 inhibitor treatment with expression and degranulation readouts\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq establishing HDAC2 binding, loss-of-function with functional granule release readout; single lab, limited mechanistic depth on SH3BP1 itself\",\n      \"pmids\": [\"39832064\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3BP1 is a BAR domain-containing RhoGAP that inactivates Rac1 and Cdc42 at specific subcellular locations—the leading edge of migrating cells (via the exocyst complex), forming epithelial junctions (via a JACOP/CD2AP/CapZ scaffold), large phagocytic cups (recruited by PI3K-generated PIP3), and FEME endocytic sites (with RICH1)—to spatiotemporally control actin dynamics, membrane remodeling, and vesicle trafficking; its activity is regulated by the PACSIN2/Cobll1 axis and its transcription is directly driven by TAZ and repressed by HDAC2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3BP1 is a BAR domain-containing RhoGAP that spatiotemporally restricts the activity of the small GTPases Rac1 and Cdc42 at discrete membrane sites to coordinate actin dynamics, membrane remodeling, and vesicle trafficking [#0, #1]. At the leading edge of migrating cells it physically associates with the exocyst complex and inactivates Rac1 to organize protrusions and sustain normal migration; its loss elevates front-edge Rac1 activity and slows motility [#0]. At forming epithelial cell-cell junctions it assembles with the adaptors JACOP/paracingulin and CD2AP and the actin-capping protein CapZ to confine Cdc42 activity and enable junction assembly [#1]. The same GAP activity is deployed during large-particle phagocytosis, where PI3K-generated PtdIns(3,4,5)P3 recruits SH3BP1 to the phagocytic cup to inactivate Rac and Cdc42 [#2], and at fast endophilin-mediated endocytosis sites, where SH3BP1 together with RICH1 locally deactivates GTP-loaded Cdc42 to drive the transient cycling of endophilin spots [#4]. SH3BP1 also operates downstream of Sema3E–PlexinD1 signaling, binding PlexinD1 and lowering Rac1 activity to mediate cell collapse [#3]. Its activity is gated by PACSIN2, which binds and inhibits SH3BP1 until Cobll1 competitively displaces PACSIN2 to release Rac1 signaling [#6], while its transcription is directly driven by the Hippo effector TAZ [#7] and repressed by HDAC2 [#8].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established SH3BP1 as a RhoGAP that links the exocyst to localized Rac1 inactivation, answering how cells spatially confine GTPase activity at the migrating front.\",\n      \"evidence\": \"Co-IP with exocyst components, FRET-based Rac1 biosensors, RNAi knockdown with rescue by constitutively active Rac1\",\n      \"pmids\": [\"21658605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of exocyst association not resolved\", \"Whether Cdc42 is also a target at the leading edge not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed SH3BP1 confines Cdc42 activity at nascent epithelial junctions through a defined adaptor/capping-protein scaffold, extending its GAP role to junction assembly and morphogenesis.\",\n      \"evidence\": \"siRNA functional screen, reciprocal Co-IP of the SH3BP1/JACOP/CD2AP/CapZ complex, Cdc42 activity assays, live junction imaging\",\n      \"pmids\": [\"22891260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the scaffold is recruited to remodeling sites not defined\", \"Direct binding topology within the complex not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Characterized a brain-specific splice variant (BGIN) fusing SH3BP1 BAR/GAP domains to a partial phosphatase domain, linking membrane-targeted Rac1 inactivation to suppression of Nox1-dependent ROS.\",\n      \"evidence\": \"MS-confirmed splice variant, subcellular fractionation, poly-Ub binding assays, Rac1 activity and ROS measurements, colocalization in AD brain tissue\",\n      \"pmids\": [\"23223568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural validation of the fusion product\", \"Physiological prevalence and function of BGIN in normal brain unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SH3BP1 downstream of Sema3E–PlexinD1 as a Rac1-suppressing effector mediating cell collapse, connecting it to guidance receptor signaling.\",\n      \"evidence\": \"Genome-wide image-based RNAi screen, Co-IP with PlexinD1, Rac1 activity assays upon knockdown\",\n      \"pmids\": [\"24841563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect PlexinD1 binding not distinguished\", \"In vivo relevance to axon guidance not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that PI3K-generated PIP3 recruits SH3BP1 to large phagocytic cups to inactivate Rac and Cdc42, explaining the size-selective requirement for GAP activity in phagocytosis.\",\n      \"evidence\": \"RhoGAP family siRNA screen, large vs. small particle phagocytosis assays, live imaging of GAP and PIP3 distribution, PI3K inhibitor epistasis\",\n      \"pmids\": [\"26465210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SH3BP1 binds PIP3 directly or via partners not resolved\", \"Redundancy with ARHGAP12/ARHGAP25 not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SH3BP1 as a direct transcriptional target of TAZ, providing a transcriptional route by which Hippo signaling drives migration.\",\n      \"evidence\": \"Luciferase reporter and ChIP assays, siRNA knockdown in TAZ-overexpressing prostate cancer cells with migration assays\",\n      \"pmids\": [\"28408625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link to GAP catalytic activity in this context not shown\", \"Generality beyond prostate cancer cells untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SH3BP1 with RICH1 locally deactivates Cdc42 at FEME sites, tying the GAP to the rapid assembly/disassembly cycling of endophilin spots.\",\n      \"evidence\": \"Colocalization screen of 65 BAR-domain proteins, live imaging of Cdc42 activity at FEME sites, RICH1/SH3BP1 knockdown with FEME readout\",\n      \"pmids\": [\"30061681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional relationship between SH3BP1 and RICH1 not biochemically defined\", \"Abstract-level mechanistic detail limits depth\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an upstream regulatory switch in which PACSIN2 binds and inhibits SH3BP1 until Cobll1 competitively displaces it, controlling Rac1 signaling and CML therapy resistance.\",\n      \"evidence\": \"Reciprocal Co-IP, competitive binding assays, Rac1 activity assays, siRNA knockdown with apoptosis/resistance readouts\",\n      \"pmids\": [\"35352878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of competitive binding not resolved\", \"Whether inhibition acts on GAP catalysis or localization unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SH3BP1 to neutrophil primary granule release and showed its expression is repressed by promoter-bound HDAC2, extending its role to immune cell degranulation.\",\n      \"evidence\": \"Microarray and ChIP-seq in patient neutrophils, siRNA knockdown in HL-60 cells with granule release assays, HDAC2 inhibitor treatment\",\n      \"pmids\": [\"39832064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic role of SH3BP1 GAP activity in degranulation not defined\", \"Whether granule effect is GTPase-dependent untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SH3BP1 is selectively targeted to distinct membrane compartments and whether a single structural mechanism integrates its BAR-domain membrane binding with substrate (Rac1 vs. Cdc42) choice remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SH3BP1 BAR/GAP architecture in the corpus\", \"Determinants of Rac1 vs. Cdc42 selectivity across sites undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [\"exocyst\", \"SH3BP1/JACOP/CD2AP/CapZ junctional complex\"],\n    \"partners\": [\"EXOC (exocyst)\", \"CGN/JACOP\", \"CD2AP\", \"CAPZ\", \"PLXND1\", \"RICH1\", \"PACSIN2\", \"COBLL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}