Affinage

SH3BP1

SH3 domain-binding protein 1 · UniProt Q9Y3L3

Length
701 aa
Mass
75.7 kDa
Annotated
2026-06-10
25 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

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

    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

    PMID:21658605

    Open questions at the time
    • Structural basis of exocyst association not resolved
    • Whether Cdc42 is also a target at the leading edge not addressed
  2. 2012 High

    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

    PMID:22891260

    Open questions at the time
    • How the scaffold is recruited to remodeling sites not defined
    • Direct binding topology within the complex not mapped
  3. 2012 Medium

    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

    PMID:23223568

    Open questions at the time
    • No structural validation of the fusion product
    • Physiological prevalence and function of BGIN in normal brain unclear
  4. 2014 Medium

    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

    PMID:24841563

    Open questions at the time
    • Direct vs. indirect PlexinD1 binding not distinguished
    • In vivo relevance to axon guidance not tested
  5. 2015 High

    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

    PMID:26465210

    Open questions at the time
    • Whether SH3BP1 binds PIP3 directly or via partners not resolved
    • Redundancy with ARHGAP12/ARHGAP25 not fully dissected
  6. 2017 Medium

    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

    PMID:28408625

    Open questions at the time
    • Link to GAP catalytic activity in this context not shown
    • Generality beyond prostate cancer cells untested
  7. 2018 Medium

    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

    PMID:30061681

    Open questions at the time
    • Functional relationship between SH3BP1 and RICH1 not biochemically defined
    • Abstract-level mechanistic detail limits depth
  8. 2022 Medium

    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

    PMID:35352878

    Open questions at the time
    • Structural basis of competitive binding not resolved
    • Whether inhibition acts on GAP catalysis or localization unclear
  9. 2025 Medium

    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

    PMID:39832064

    Open questions at the time
    • Mechanistic role of SH3BP1 GAP activity in degranulation not defined
    • Whether granule effect is GTPase-dependent untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of SH3BP1 BAR/GAP architecture in the corpus
  • Determinants of Rac1 vs. Cdc42 selectivity across sites undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CAPZCD2APCGN/JACOPCOBLL1EXOC (EXOCYST)PACSIN2PLXND1RICH1
Complex memberships
SH3BP1/JACOP/CD2AP/CapZ junctional complexexocyst

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 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. 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 Molecular cell High 21658605
2012 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. siRNA functional screen, co-immunoprecipitation of the SH3BP1/JACOP/CD2AP/CapZ complex, Cdc42 activity assays, live imaging of junction formation upon SH3BP1 depletion The Journal of cell biology High 22891260
2015 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. 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 Nature communications High 26465210
2014 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. Image-based genome-wide RNAi screen, co-immunoprecipitation of SH3BP1 with PlexinD1, Rac1 activity assays upon SH3BP1 knockdown The Journal of cell biology Medium 24841563
2018 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. 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 Nature cell biology Medium 30061681
2012 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. 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 Molecular biology of the cell Medium 23223568
2022 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. Co-immunoprecipitation demonstrating PACSIN2–SH3BP1 and Cobll1–PACSIN2 interactions, competitive binding assays, Rac1 activity assays, siRNA knockdown with apoptosis and resistance readouts Cancer medicine Medium 35352878
2017 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. Luciferase reporter and ChIP assays establishing SH3BP1 as a direct TAZ target gene, siRNA knockdown of SH3BP1 in TAZ-overexpressing cells with migration assays The Journal of biological chemistry Medium 28408625
2025 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. 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 Molecular neurobiology Medium 39832064

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins. Nature communications 173 26465210
2014 Epithelial junctions and Rho family GTPases: the zonular signalosome. Small GTPases 146 25483301
2014 The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases 98 25469537
2018 FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis. Nature cell biology 78 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 66 22891260
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 46 28408625
2017 A family affair: A Ral-exocyst-centered network links Ras, Rac, Rho signaling to control cell migration. Small GTPases 32 28498728
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
2016 SH3-domain binding protein 1 in the tumor microenvironment promotes hepatocellular carcinoma metastasis through WAVE2 pathway. Oncotarget 23 26933917
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 Screening of Important Markers in Peripheral Blood Mononuclear Cells to Predict Female Osteoporosis Risk Using LASSO Regression Algorithm and SVM Method. Evolutionary bioinformatics online 7 35110962
2022 Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia. Cancer medicine 7 35352878
2020 RhoGAP RGA-8 supports morphogenesis in C. elegans by polarizing epithelia. Biology open 5 33243762
2025 Multi-omics unravel heterogeneity of glucose metabolism reprogramming in gastric cancer. Clinical and experimental medicine 3 41249595
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 Molecular Mediators of Neutrophil Primary Granule Release Following Acute Ischemic Stroke and their Associated Epigenetic Modulation by HDAC2. Molecular neurobiology 0 39832064

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