Affinage

SH3BP1

SH3 domain-binding protein 1 · UniProt Q9Y3L3

Round 2 corrected
Length
701 aa
Mass
75.7 kDa
Annotated
2026-04-28
55 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SH3BP1 is a BAR-domain-containing RhoGAP that spatiotemporally inactivates Rac1 and Cdc42 at discrete membrane sites to coordinate actin-dependent cellular processes including cell migration, junction assembly, phagocytosis, and endocytosis. At the leading edge of migrating cells, SH3BP1 associates with the exocyst complex and limits Rac1 activity to stabilize protrusions and enable directional migration (PMID:21658605); at epithelial junctions, it forms a complex with JACOP/paracingulin, CD2AP, and CapZ to spatially confine Cdc42 activity during junction maturation (PMID:22891260). SH3BP1 is recruited to large phagocytic cups via PI3K-generated PIP3, where it cooperates with ARHGAP12 and ARHGAP25 to inactivate Rac/Cdc42 for phagocytic closure (PMID:26465210), and participates in fast endophilin-mediated endocytosis by locally deactivating Cdc42-recruited F-BAR proteins (PMID:30061681). SH3BP1 activity is negatively regulated by PACSIN2, which is relieved by competitive displacement from Cobll1 (PMID:35352878), and its transcription is driven by TAZ in the context of cell migration (PMID:28408625).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    The first mechanistic study established that SH3BP1 functions as a Rac1-directed GAP at the cell leading edge, answering how local Rac1 cycling is achieved during migration and linking SH3BP1 to the exocyst complex.

    Evidence Co-immunoprecipitation with exocyst subunits, FRET-based Rac1 biosensors, RNAi knockdown with morphodynamics analysis, and epistasis with constitutively active Rac1 in motile cells

    PMID:21658605

    Open questions at the time
    • Structural basis of SH3BP1–exocyst interaction unknown
    • Whether SH3BP1 GAP activity toward Cdc42 operates at the leading edge was not tested
    • Upstream signals activating SH3BP1 at the cell front were not identified
  2. 2012 High

    SH3BP1 was shown to confine Cdc42 activity at epithelial junctions through a dedicated JACOP–CD2AP–CapZ complex, establishing that its GAP activity extends beyond Rac1 to Cdc42 and operates in a junctional context distinct from the migratory leading edge.

    Evidence Functional siRNA screen, reciprocal Co-IP identifying the quaternary complex, Cdc42 biosensor readout, and live-cell imaging of junction formation

    PMID:22891260

    Open questions at the time
    • How the junctional complex is spatially separated from the exocyst-associated pool is unclear
    • Direct GAP kinetics for Cdc42 were not measured in vitro
  3. 2012 Medium

    Identification of a brain-specific splice variant (BGIN) from the SH3BP1 locus revealed a poly-ubiquitin-binding module that targets the protein to membrane-associated Rac1, suppressing Nox1-dependent ROS, with possible relevance to Alzheimer's disease pathology.

    Evidence Splice variant characterization, subcellular fractionation, Rac1 activity assay, co-localization in AD brain tissue

    PMID:23223568

    Open questions at the time
    • BGIN function has not been confirmed by independent laboratories
    • The physiological significance of the poly-ubiquitin-binding module requires further biochemical reconstitution
    • Causal role in AD pathogenesis is not established
  4. 2014 High

    A genome-wide RNAi screen placed SH3BP1 downstream of Semaphorin 3E–PlexinD1 signaling, showing that receptor-mediated Rac1 inactivation during cell collapse requires SH3BP1 GAP activity.

    Evidence Genome-wide image-based RNAi screen, Co-IP with PlexinD1, Rac1 activity assay, cell collapse phenotype

    PMID:24841563

    Open questions at the time
    • Whether PlexinD1 directly phosphorylates or allosterically activates SH3BP1 is unknown
    • In vivo relevance in semaphorin-mediated axon guidance not tested
  5. 2015 High

    SH3BP1 was demonstrated to function in size-selective phagocytosis, recruited to large phagocytic cups by PIP3 and cooperating with ARHGAP12 and ARHGAP25 to inactivate Rac/Cdc42 for cup closure, resolving how PI3K signaling is coupled to GTPase deactivation during phagocytosis.

    Evidence Systematic screen of 62 RhoGAPs, siRNA knockdown with phagocytosis assay for particles of varying size, PI3K inhibition epistasis, GTPase activity measurement

    PMID:26465210

    Open questions at the time
    • Relative contribution of the three GAPs and their potential redundancy not fully dissected
    • Mechanism of PIP3-mediated SH3BP1 recruitment (direct lipid binding vs adaptor) not resolved
  6. 2017 Medium

    SH3BP1 transcription was shown to be directly regulated by the Hippo pathway effector TAZ, linking Hippo signaling to Rho GTPase control during cell migration.

    Evidence ChIP at SH3BP1 promoter, luciferase reporter, siRNA knockdown with migration rescue in prostate cancer cells

    PMID:28408625

    Open questions at the time
    • Whether YAP also drives SH3BP1 transcription was not tested
    • ETS factor identity cooperating with TAZ at the promoter not fully resolved
  7. 2018 Medium

    SH3BP1 was positioned in the fast endophilin-mediated endocytosis (FEME) cycle, where it deactivates Cdc42 to disassemble FBP17/CIP4 scaffolds and prime the membrane for cargo internalization.

    Evidence Live-cell fluorescence imaging of endophilin spots, siRNA knockdown, co-localization analysis, GTPase activity assays

    PMID:30061681

    Open questions at the time
    • Relative importance of SH3BP1 versus RICH1 in FEME not quantified
    • Direct biochemical interaction with endophilin not demonstrated
  8. 2020 Medium

    The C. elegans ortholog RGA-8 confirmed an evolutionarily conserved role for SH3BP1-family GAPs in controlling CDC-42/actin dynamics during morphogenetic cell migration, validating the mammalian findings in an in vivo genetic system.

    Evidence Genetic epistasis with CDC-42 pathway (WASP-1, TOCA-1/2), live imaging of ventral enclosure, loss-of-function analysis

    PMID:33243762

    Open questions at the time
    • RGA-8 is also homologous to RICH1/ARHGAP17, so specific equivalence to mammalian SH3BP1 is uncertain
    • No rescue with human SH3BP1 was performed
  9. 2022 Medium

    PACSIN2 was identified as a direct negative regulator of SH3BP1, with Cobll1 competitively releasing SH3BP1 from inhibition to activate Rac1 signaling and confer TKI resistance in CML, establishing the first post-translational regulatory axis controlling SH3BP1 GAP activity.

    Evidence Co-IP, competitive binding assays, Rac1 activity measurements, siRNA knockdown, apoptosis assays in CML cells

    PMID:35352878

    Open questions at the time
    • Whether PACSIN2 inhibits SH3BP1 by sequestering the BAR domain or the GAP domain is not resolved
    • Clinical relevance of the Cobll1-PACSIN2-SH3BP1 axis in TKI resistance needs patient-level validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SH3BP1's BAR-domain membrane targeting, how SH3BP1 is partitioned among its multiple functional pools (exocyst, junctional, phagocytic, endocytic), and whether SH3BP1 loss produces phenotypes in knockout animal models.
  • No crystal or cryo-EM structure of SH3BP1
  • No knockout mouse or zebrafish phenotype reported
  • In vivo substrate preference (Rac1 vs Cdc42) in different tissues unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 7 GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2 R-HSA-1500931 Cell-Cell communication 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CD2APCDC42CGNL1COBLL1PACSIN2PLXND1RAC1
Complex memberships
Exocyst complex (via interaction)JACOP–CD2AP–CapZ junctional complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SH3BP1 was identified as a binding partner of the exocyst complex and shown to localize to the leading edge of motile cells, where its RhoGAP activity toward Rac1 is required for cell migration. Loss of SH3BP1 caused abnormally high Rac1 activity at the cell front, disorganized and unstable protrusions, and impaired migration, phenocopied by constitutively active Rac1. Co-immunoprecipitation, FRET-based Rac1 biosensors in live cells, RNAi knockdown with morphodynamics analysis, epistasis with constitutively active Rac1 Molecular cell High 21658605
2012 SH3BP1 forms a complex with JACOP/paracingulin and CD2AP at epithelial junctions; this complex recruits the actin-capping protein CapZ. The SH3BP1–JACOP–CD2AP–CapZ complex is required to spatially confine Cdc42 activity during junction assembly, and its depletion causes loss of spatial Cdc42 control, stalled membrane remodeling, and enhanced filopodia growth. siRNA functional screen, Co-immunoprecipitation, Cdc42 activity reporters, live-cell imaging of junction formation in epithelial cells The Journal of cell biology High 22891260
2014 SH3BP1 was identified as a key downstream effector of Semaphorin 3E–PlexinD1 signaling through a genome-wide image-based RNAi screen. SH3BP1 interacts with PlexinD1 and mediates Sema3E-induced cell collapse by regulating Rac1 activity. Genome-wide image-based RNAi screen, co-immunoprecipitation with PlexinD1, Rac1 activity assay, loss-of-function with cell collapse readout The Journal of cell biology High 24841563
2015 SH3BP1 (together with ARHGAP12 and ARHGAP25) is recruited to large phagocytic cups by PI3K-generated phosphatidylinositol 3,4,5-trisphosphate, where it synergistically inactivates Rac and Cdc42 to enable completion of large-particle phagocytosis. Silencing SH3BP1 impairs phagocytosis of large but not small targets, establishing its PI3K-dependent, size-selective role. RhoGAP siRNA screen (62 family members), RhoGAP knockdown with phagocytosis assay, PI3K inhibition, GTPase activity measurement, fluorescence imaging of phagosomal phosphoinositides Nature communications High 26465210
2018 At sites of fast endophilin-mediated endocytosis (FEME), membrane-bound GTP-loaded Cdc42 recruits FBP17 and CIP4, which are then locally deactivated by RICH1 and SH3BP1 GTPase-activating proteins, generating transient assembly and disassembly of endophilin spots that prime the membrane for FEME. Live-cell fluorescence imaging, siRNA knockdown, co-localization of SH3BP1 with endophilin spots, GTPase activity assays Nature cell biology Medium 30061681
2012 A brain-specific splice variant termed BARGIN (BGIN) comprises sequences from the SH3BP1 locus combined with partial CIN phosphatase domain sequences. BGIN contains a poly-ubiquitin-binding module that directs it to membranous fractions, where it inactivates a membrane-localized Rac1 population to suppress Nox1-dependent ROS generation; BGIN/poly-Ub interactions are observed in Alzheimer's disease tangle aggregates. Characterization of splice variant, subcellular fractionation, Rac1 activity assay, co-localization in AD brain tissue, APP proteotoxicity cell model with BGIN knockdown Molecular biology of the cell Medium 23223568
2022 PACSIN2 binds and inhibits SH3BP1; when Cobll1 is present, it competes with SH3BP1 for PACSIN2 binding with higher affinity, releasing SH3BP1 to activate the Rac1 pathway and suppress TKI-induced apoptosis in chronic myeloid leukemia, leading to drug resistance. Co-immunoprecipitation, competitive binding assays, Rac1 activity assays, siRNA knockdown, apoptosis assays in CML cells Cancer medicine Medium 35352878
2017 SH3BP1 was identified as a direct transcriptional target of TAZ in prostate cancer cells, mediating TAZ-induced enhancement of cell migration through its RhoGAP activity. Luciferase reporter assay, ChIP, siRNA knockdown of SH3BP1 with migration assay rescue experiment The Journal of biological chemistry Medium 28408625
2020 A comprehensive RNAi screen of 66 Rho-GAP family members in human mammary epithelial cells identified SH3BP1 as one of at least two RhoGAPs critically regulating epithelial cell morphology and suppression of EMT-like phenotypes. Genome-wide RhoGAP siRNA screen, cell morphology analysis, EMT marker expression FASEB journal Low 32378260
2025 SH3BP1, SYT9, and STXBP1 were identified as mediators of neutrophil primary granule release following acute ischemic stroke, with HDAC2 binding to their promoter/intron/upstream regions to epigenetically regulate their expression; knockdown of SH3BP1 impaired primary granule release in vitro. Microarray and ChIP-seq in patient neutrophils, siRNA knockdown in HL-60 cells with degranulation assay, HDAC2 inhibition experiments Molecular neurobiology Medium 39832064
2020 C. elegans RGA-8, a homolog of SH3BP1/RICH1/ARHGAP17, uses its BAR and RhoGAP domains to regulate CDC-42 activity, thereby controlling F-actin levels and myosin enrichment in migrating epidermal cells during ventral enclosure; loss of RGA-8 alters membrane recruitment of active CDC-42. Genetic epistasis with CDC-42 pathway components (WASP-1/WSP-1, TOCA-1/TOCA-2), live imaging, RGA-8 localization studies, loss-of-function morphogenesis phenotype analysis Biology open Medium 33243762

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular systems biology 419 16729043
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2015 Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins. Nature communications 170 26465210
2014 Epithelial junctions and Rho family GTPases: the zonular signalosome. Small GTPases 144 25483301
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2021 A protein interaction landscape of breast cancer. Science (New York, N.Y.) 111 34591612
2014 The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases 98 25469537
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2018 FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis. Nature cell biology 77 30061681
2011 SH3BP1, an exocyst-associated RhoGAP, inactivates Rac1 at the front to drive cell motility. Molecular cell 67 21658605
2012 Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex. The Journal of cell biology 65 22891260
2023 SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication. Scientific reports 48 37640791
2020 RIG-I regulates myeloid differentiation by promoting TRIM25-mediated ISGylation. Proceedings of the National Academy of Sciences of the United States of America 47 32513696
2019 Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming Reveals Regulators of the Respirasome and Neurogenesis. iScience 45 31536960
2017 ETS (E26 transformation-specific) up-regulation of the transcriptional co-activator TAZ promotes cell migration and metastasis in prostate cancer. The Journal of biological chemistry 45 28408625
2015 SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor. Clinical cancer research : an official journal of the American Association for Cancer Research 42 26286913
2020 ZZW-115-dependent inhibition of NUPR1 nuclear translocation sensitizes cancer cells to genotoxic agents. JCI insight 38 32780723
2019 PRISMA: Protein Interaction Screen on Peptide Matrix Reveals Interaction Footprints and Modifications- Dependent Interactome of Intrinsically Disordered C/EBPβ. iScience 35 30884312
2017 A family affair: A Ral-exocyst-centered network links Ras, Rac, Rho signaling to control cell migration. Small GTPases 32 28498728
2023 TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing. Neuro-oncology 25 36215168
2014 An image-based RNAi screen identifies SH3BP1 as a key effector of Semaphorin 3E-PlexinD1 signaling. The Journal of cell biology 25 24841563
2020 Comprehensive analysis on the whole Rho-GAP family reveals that ARHGAP4 suppresses EMT in epithelial cells under negative regulation by Septin9. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 32378260
2017 SH3BP1-induced Rac-Wave2 pathway activation regulates cervical cancer cell migration, invasion, and chemoresistance to cisplatin. Journal of cellular biochemistry 24 28786507
2005 NMR structure and regulated expression in APL cell of human SH3BGRL3. FEBS letters 24 15907482
2016 SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway. Oncotarget 23 26933917
2018 Alterations in the brain interactome of the intrinsically disordered N-terminal domain of the cellular prion protein (PrPC) in Alzheimer's disease. PloS one 21 29791485
2021 ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ. Human molecular genetics 20 33729478
2018 Quantitative mapping of RNA-mediated nuclear estrogen receptor β interactome in human breast cancer cells. Scientific data 20 29509190
2024 Hexosaminidase B-driven cancer cell-macrophage co-dependency promotes glycolysis addiction and tumorigenesis in glioblastoma. Nature communications 19 39353936
2022 HDLBP Promotes Hepatocellular Carcinoma Proliferation and Sorafenib Resistance by Suppressing Trim71-dependent RAF1 Degradation. Cellular and molecular gastroenterology and hepatology 19 36244648
1999 Identification, characterization, and cloning of TIP-B1, a novel protein inhibitor of tumor necrosis factor-induced lysis. Cancer research 19 10554026
2012 A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation. Molecular biology of the cell 15 23223568
2022 Development and validation of an RNA sequencing panel for gene fusions in soft tissue sarcoma. Cancer science 13 35238118
2022 Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia. Cancer medicine 7 35352878
2022 Screening of Important Markers in Peripheral Blood Mononuclear Cells to Predict Female Osteoporosis Risk Using LASSO Regression Algorithm and SVM Method. Evolutionary bioinformatics online 5 35110962
2020 RhoGAP RGA-8 supports morphogenesis in C. elegans by polarizing epithelia. Biology open 4 33243762
2023 Ascertaining the genetic background of the Celtic-Iberian pig strain: A signatures of selection approach. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 3 37807719
2025 Terahertz Irradiation Promotes Angiogenesis in vitro by Enhancing Permeability of the Voltage-Gated Calcium Channel. PloS one 2 39982926
2023 SH3BP1 Regulates Melanoma Progression Through Race1/Wace2 Signaling Pathway. Clinical Medicine Insights. Oncology 2 37114076
2026 Seco-neokadsuranic acid A antagonizes SH3BP1 to suppress hepatocellular carcinoma progression through PPAR pathway activation. Phytomedicine : international journal of phytotherapy and phytopharmacology 1 41558058
2025 Exploring potential therapeutic targets for colorectal tumors based on whole genome sequencing of colorectal tumors and paracancerous tissues. Frontiers in molecular biosciences 1 40688112
2025 Estimation of genome-wide patterns of homozygosity, heterozygosity and inbreeding in crossbred dairy cattle population in Pakistan. Tropical animal health and production 1 41003855
2025 Multi-omics unravel heterogeneity of glucose metabolism reprogramming in gastric cancer. Clinical and experimental medicine 1 41249595
2025 Molecular Mediators of Neutrophil Primary Granule Release Following Acute Ischemic Stroke and their Associated Epigenetic Modulation by HDAC2. Molecular neurobiology 0 39832064