Affinage

SRGAP3

SLIT-ROBO Rho GTPase-activating protein 3 · UniProt O43295

Length
1099 aa
Mass
124.5 kDa
Annotated
2026-06-10
23 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SRGAP3 (WRP/MEGAP) is a Rac1-selective RhoGAP that couples Slit-Robo guidance signaling to actin cytoskeletal remodeling, governing neuronal migration, dendritic spine morphogenesis, neuronal differentiation, and cell migration (PMID:12447388, PMID:12195014, PMID:22820399). It binds the activated GTP-bound form of Rac1 through its RhoGAP domain and accelerates GTP hydrolysis; the catalytic arginine (R542) is essential, as its mutation abolishes effects on actin and microtubule dynamics, cell migration, and neuronal differentiation (PMID:16730001, PMID:21350945). Through its SH3 domain SRGAP3 binds WAVE-1 to form a Rac signal-termination complex, an anchoring that is required in vivo for normal dendritic spine density, synaptic plasticity, and cognitive behavior (PMID:12447388, PMID:17215396). Its F-BAR domain deforms membrane to localize the protein to the leading edge and induce filopodia, while the SH3 domain targets it to focal adhesions, and a C-terminal PXXP motif links it to endocytic SH3 proteins (Amphiphysin, Endophilin-A1/A2) and Grb2 (PMID:22159416, PMID:22467852, PMID:25819436). SRGAP3 acts downstream of Slit-Robo, interacting with Robo1/Robo2 to position post-crossing commissural axons and to suppress neuronal differentiation through Rac1 (PMID:21655271, PMID:23505444), and a nuclear pool engages the SWI/SNF ATPase Brg1 to influence dendrite complexity and differentiation (PMID:24561795). Loss of Srgap3 in mice elevates basal Rac1 activity and produces aberrant neural progenitor migration, hydrocephalus, abnormal spines, and behavioral deficits (PMID:23007397, PMID:22820399). Beyond these neural roles it acts as a Rac1-suppressing tumor suppressor in mammary epithelium, restraining anchorage-independent growth and invasion via downstream Rho/ROCK signaling (PMID:23108406).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 High

    Established SRGAP3 as a Rac-selective GAP and defined its molecular context by placing it within the WAVE-1 complex as a Rac signal-termination factor, answering how Rac signaling is locally attenuated.

    Evidence Tandem mass spectrometry, SH3-domain direct binding assay, and in vivo Rac activity assay identifying WRP in the WAVE-1 complex; parallel in vitro GAP assay for MEGAP/srGAP3

    PMID:12195014 PMID:12447388

    Open questions at the time
    • Slit-Robo pathway placement cited from prior work rather than directly demonstrated
    • structural basis of SH3-WAVE-1 binding not resolved
  2. 2006 High

    Demonstrated that catalytic GAP activity is required for SRGAP3's control of cytoskeletal dynamics and migration, linking enzymatic function to phenotype through the R542 active-site residue.

    Evidence Inducible expression in SH-SY5Y cells, time-lapse microscopy, R542I active-site mutagenesis, and epistasis rescue with constitutively active Rac1/Cdc42

    PMID:16730001

    Open questions at the time
    • mechanism of microtubule and focal-complex effects relative to direct Rac GAP activity not separated
    • single cell-line context
  3. 2007 High

    Showed in vivo that the SRGAP3-WAVE-1 interaction is a homeostatic requirement for synaptic connectivity and cognition, elevating the biochemical complex to a developmental mechanism.

    Evidence Gene targeting in mice disrupting WRP-WAVE-1 binding with imaging, electrophysiology, and behavioral readouts

    PMID:17215396

    Open questions at the time
    • does not isolate WAVE-1-dependent from WAVE-1-independent SRGAP3 functions in vivo
  4. 2011 Medium

    Resolved domain-level division of labor — F-BAR targets the leading edge and SH3 targets focal adhesions — and identified lamellipodin and Robo1/Robo2 as physical partners controlling protrusion and axon positioning.

    Evidence Co-immunoprecipitation, live-cell imaging, domain localization, srGAP3 KO MEFs with lamellipodin rescue, immunohistochemistry, and axon tracing in KO mice

    PMID:21350945 PMID:21655271 PMID:22159416

    Open questions at the time
    • how F-BAR and SH3 localizations are coordinated in a single molecule unresolved
    • direct Robo-to-Rac signaling chain not reconstituted
  5. 2012 Medium

    Established SRGAP3 as a negative regulator of Rac1 in vivo during brain development and as a tumor suppressor, broadening its role from neurons to epithelial growth control, and characterized F-BAR-driven filopodia induction.

    Evidence Srgap3 KO mice with Rac1 activity assays, lineage tracing, histology/MRI; breast cancer re-expression with GAP-dead mutant and ROCK inhibition; F-BAR FRAP and heterodimerization assays

    PMID:22467852 PMID:22820399 PMID:23007397 PMID:23108406

    Open questions at the time
    • tumor suppressor mechanism (Rac1 vs Rho/ROCK balance) not fully dissected
    • F-BAR filopodia potency differences mechanistically unexplained
  6. 2013 Medium

    Placed SRGAP3-Rac1 signaling downstream of Slit-Robo as an inhibitor of neuronal differentiation, integrating the GAP into a defined guidance pathway shared with srGAP1/2.

    Evidence Overexpression/knockdown in Neuro2A cells, Slit-Robo pathway inhibition, and GAP-dead mutant epistasis

    PMID:23505444

    Open questions at the time
    • direct Robo-to-srGAP3 activation step not biochemically demonstrated
  7. 2014 Medium

    Identified a nuclear function for SRGAP3 through interaction with the SWI/SNF ATPase Brg1, suggesting a route by which a cytoskeletal GAP influences gene-regulatory programs.

    Evidence Co-immunoprecipitation, domain deletion mapping (C-terminus / Brg1 ATPase motif), neuronal morphology and Neuro2A differentiation assays

    PMID:24561795

    Open questions at the time
    • target genes regulated by nuclear srGAP3-Brg1 not identified
    • Rac1/GAP-43 as mediators only proposed, not mechanistically established
  8. 2015 Medium

    Mapped a single C-terminal PXXP motif that links SRGAP3 to endocytic SH3 proteins and Grb2, providing a candidate connection between receptor signaling and membrane trafficking.

    Evidence Pulldown and PXXP mutational analysis against SH3 domains of Amphiphysin, Endophilin-A1/A2, and Grb2

    PMID:25819436

    Open questions at the time
    • functional consequence of endocytic coupling in cells not demonstrated
    • no in vivo validation
  9. 2020 Medium

    Demonstrated phase-specific regulation of dendritic spines by SRGAP3 in neuropathic pain, showing that its level dynamically tunes Rac1 activity to control spine maturation and pain behavior.

    Evidence srGAP3 siRNA and Rac1 inhibitor with Rac1-GTP Western blotting, Golgi spine staining, and behavioral assays in a paclitaxel neuropathy model

    PMID:32237255

    Open questions at the time
    • upstream control of srGAP3 level across pain phases unknown
    • single model and lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SRGAP3's distinct domain activities (F-BAR membrane deformation, GAP catalysis, SH3/PXXP partner binding, and nuclear Brg1 engagement) are spatially and temporally coordinated within a single signaling event, and what gene-regulatory targets the nuclear pool controls.
  • no integrated structural/regulatory model across domains
  • nuclear transcriptional targets uncharacterized
  • regulation of SRGAP3 abundance and localization not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 1
Partners
AMPHGRB2RAC1RAPH1ROBO1ROBO2SMARCA4WASF1
Complex memberships
WAVE-1 complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 WRP (SRGAP3) was identified as a component of the WAVE-1 signaling complex via tandem mass spectrometry. WRP binds directly to WAVE-1 through its SH3 domain and functions as a Rac-selective GTPase-activating protein that attenuates Rac signaling, acting as a signal termination factor for Rac within the WAVE-1 complex. Tandem mass spectrometry, direct binding assay (SH3 domain interaction), in vivo Rac activity assay Nature cell biology High 12447388
2002 MEGAP/srGAP3 (isoforms a and b) functions as a GTPase-activating protein (GAP) in vitro, as demonstrated by in vitro GAP assay, and acts downstream of the Slit-Robo pathway to regulate neuronal migration and axonal branching. In vitro GAP assay, FISH, LOH analysis Proceedings of the National Academy of Sciences of the United States of America Medium 12195014
2006 MEGAP/srGAP3 negatively regulates cell migration by perturbing actin and microtubule cytoskeleton dynamics and hindering focal complex formation. The GAP domain (residue R542) is required for this function, as R542I missense mutation abolishes effects on actin, microtubule remodeling, and cell migration. Constitutively active Rac1 and Cdc42 rescue the loss of filopodia/lamellipodia caused by MEGAP overexpression. Inducible expression in SH-SY5Y neuroblastoma cells, time-lapse microscopy, active-site mutagenesis (R542I), epistasis with constitutively active Rac1/Cdc42 Experimental cell research High 16730001
2007 WRP (SRGAP3) anchoring to WAVE-1 is required for normal dendritic spine density, synaptic plasticity, and cognitive behavior. Gene targeting in mice disrupting WRP-WAVE-1 interaction demonstrated that this complex is a homeostatic mechanism for neuronal development and synaptic connectivity. Neuronal time-lapse imaging, behavioral analyses, electrophysiological recordings, gene targeting in mice The Journal of neuroscience High 17215396
2011 srGAP3 interacts with lamellipodin at the leading edge of cellular protrusions. The F-BAR domain localizes srGAP3 to the leading edge while the SH3 domain targets srGAP3 to focal adhesions. srGAP3 inhibits lamellipodin-evoked lamellipodial dynamics, and knockout fibroblasts display increased cell area and lamellipodia formation rescued by lamellipodin knockdown. Co-immunoprecipitation, live-cell imaging, domain localization studies, srGAP3 knockout MEFs, shRNA knockdown of lamellipodin Journal of cell science High 22159416
2011 srGAP3 interacts with Robo1 and Robo2 (Slit receptors), co-localizing with Robo1 in the ventral/lateral funiculus and Robo2 in the lateral funiculus of the spinal cord. Loss of srGAP3 in KO mice causes thickening of the ventral funiculus and thinning of the lateral funiculus, indicating a role in lateral positioning of post-crossing commissural axons. Co-immunoprecipitation, immunohistochemistry, axon tracing in KO mice PloS one Medium 21655271
2011 srGAP3 selectively binds to the activated (GTP-bound) form of Rac1 via RhoGAP domain pulldown. Overexpression of srGAP3 inhibits neuronal differentiation in a Rac1-dependent and GAP domain-dependent manner (R542A mutation abolishes effect), and constitutively active Rac1 rescues srGAP3-mediated inhibition of differentiation. RhoGAP pulldown assay, overexpression/knockdown in Neuro2A cells, active-site mutagenesis (R542A), epistasis with CA-Rac1 Cellular and molecular neurobiology Medium 21350945
2012 The F-BAR domain of srGAP3 (F-BAR3) induces filopodia formation in COS7 cells and cortical neurons, though less potently than srGAP2. F-BAR domains of srGAP1, 2, and 3 can heterodimerize. F-BAR3 displays slower molecular dynamics at the plasma membrane than F-BAR2 as measured by FRAP, correlating with reduced filopodia induction potency. Live-cell imaging in COS7 and cortical neurons, FRAP, heterodimerization assay Journal of cell science Medium 22467852
2012 Loss of Wrp/Srgap3 in mice results in abnormal migration of neural progenitor cells from the ventricular niche into the corpus callosum, aberrant astroglial differentiation, periventricular lesions, and obstructive hydrocephalus due to cerebral aqueductal occlusion. Srgap3 knockout mice, lineage tracing, histology, MRI The Journal of biological chemistry Medium 23007397
2012 Srgap3 knockout mice show increased basal Rac1 activity, enlarged lateral ventricles, abnormal dendritic spines, and complex behavioral deficits (impaired spontaneous alternation, social behavior, prepulse inhibition), establishing srGAP3 as a negative regulator of Rac1 activity in vivo during brain development. Srgap3 KO mice, Rac1 activity assay, behavioral testing, neuroanatomical analysis FASEB journal Medium 22820399
2012 srGAP3 functions as a tumor suppressor in mammary epithelial cells by negatively regulating Rac1. Re-expression of srGAP3 (but not GAP-dead mutant) in breast cancer lines inhibits anchorage-independent growth and invasion, accompanied by increased ERM and MLC2 phosphorylation, and ROCK inhibition restores invasion, placing srGAP3 upstream of Rac1 and downstream Rho/ROCK signaling. RNAi knockdown, re-expression with GAP-dead mutant, anchorage-independent growth assay, invasion assay, phosphorylation analysis, ROCK inhibition Oncogene Medium 23108406
2013 srGAP3 inhibits neuronal differentiation downstream of Slit-Robo signaling; inhibition of Slit-Robo interaction phenocopies srGAP3 loss-of-function, and srGAP3-Rac1 signaling is required for the inhibitory effect of srGAP1 and srGAP2 on neuronal differentiation. Overexpression/knockdown in Neuro2A cells, Slit-Robo pathway inhibition, GAP-dead mutants (srGAP1 R542A, srGAP2 R527A), epistasis experiments PloS one Medium 23505444
2014 Nuclear-localized srGAP3 interacts with the SWI/SNF chromatin remodeling factor Brg1. This interaction is mediated by the C-terminal region of srGAP3 and the ATPase motif of Brg1. The interaction influences dendrite complexity in primary cortical neurons and VPA-induced neuronal differentiation in Neuro2A cells. GTP-bound Rac1 and GAP-43 are identified as potential mediators of the nuclear srGAP3-Brg1 interaction. Co-immunoprecipitation, domain deletion mapping, neuronal morphology analysis, Neuro2A differentiation assay Molecular and cellular neurosciences Medium 24561795
2014 srGAP3 interacts with Robo2 and Slit1, and this interaction decreases Rac1-GTP activity in dorsal root ganglion neurons, promoting neurite outgrowth and filopodial growth cone formation. Co-immunoprecipitation, immunoblotting for Rac1-GTP, anti-srGAP3/Robo2 antibody inhibition of neurite outgrowth Asian Pacific journal of tropical medicine Low 25149377
2015 The C-terminal region (CTR) of srGAP3 contains a single PXXP proline-rich motif that mediates binding to SH3 domains of endocytic proteins Amphiphysin, Endophilin-A2, Endophilin-A1, and the Ras signaling protein Grb2, potentially linking receptor signaling to the endocytic machinery. Pulldown assay, mutational analysis of PXXP motif, SH3 domain binding assay FEBS letters Medium 25819436
2020 In spinal cord dorsal horn during neuropathic pain, increased srGAP3 promotes new immature dendritic spine formation in the initiation phase, while decreased srGAP3 in the maintenance phase leads to elevated Rac1-GTP activity, actin polymerization, and dendritic spine maturation. srGAP3 siRNA during initiation phase, and Rac1 inhibitor during maintenance phase, each independently attenuate neuropathic pain, and combined targeting produces optimal analgesia. srGAP3 siRNA, Rac1 inhibitor, Western blotting for Rac1-GTP, Golgi staining for dendritic spines, behavioral assays in paclitaxel neuropathy model The Journal of physiology Medium 32237255

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. The Journal of neuroscience : the official journal of the Society for Neuroscience 178 17215396
2002 The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation. Proceedings of the National Academy of Sciences of the United States of America 174 12195014
2002 The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling. Nature cell biology 166 12447388
2012 The F-BAR domains from srGAP1, srGAP2 and srGAP3 regulate membrane deformation differently. Journal of cell science 64 22467852
2006 MEGAP impedes cell migration via regulating actin and microtubule dynamics and focal complex formation. Experimental cell research 50 16730001
2012 Srgap3⁻/⁻ mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 22820399
2011 SrGAP3 interacts with lamellipodin at the cell membrane and regulates Rac-dependent cellular protrusions. Journal of cell science 40 22159416
2013 The inverse F-BAR domain protein srGAP2 acts through srGAP3 to modulate neuronal differentiation and neurite outgrowth of mouse neuroblastoma cells. PloS one 36 23505444
2012 The cellular function of srGAP3 and its role in neuronal morphogenesis. Mechanisms of development 36 23127797
2012 A tumor suppressor role for srGAP3 in mammary epithelial cells. Oncogene 29 23108406
2016 Non-catalytic roles for TET1 protein negatively regulating neuronal differentiation through srGAP3 in neuroblastoma cells. Protein & cell 23 27113584
2011 A Novel Microduplication in the Neurodevelopmental Gene SRGAP3 That Segregates with Psychotic Illness in the Family of a COS Proband. Case reports in genetics 19 23074677
2011 The mental retardation associated protein, srGAP3 negatively regulates VPA-induced neuronal differentiation of Neuro2A cells. Cellular and molecular neurobiology 16 21350945
2013 The mental retardation-associated protein srGAP3 regulates survival, proliferation, and differentiation of rat embryonic neural stem/progenitor cells. Stem cells and development 15 23311320
2008 Expression of MEGAP mRNA during embryonic development. Gene expression patterns : GEP 15 18343202
2020 Distinct roles of srGAP3-Rac1 in the initiation and maintenance phases of neuropathic pain induced by paclitaxel. The Journal of physiology 14 32237255
2012 Disruption of wave-associated Rac GTPase-activating protein (Wrp) leads to abnormal adult neural progenitor migration associated with hydrocephalus. The Journal of biological chemistry 13 23007397
2015 SrGAP3 knockout mice display enlarged lateral ventricles and specific cilia disturbances of ependymal cells in the third ventricle. Cell and tissue research 12 26104135
2011 Evidence for a role of srGAP3 in the positioning of commissural axons within the ventrolateral funiculus of the mouse spinal cord. PloS one 12 21655271
2015 A single PXXP motif in the C-terminal region of srGAP3 mediates binding to multiple SH3 domains. FEBS letters 10 25819436
2014 A link between the nuclear-localized srGAP3 and the SWI/SNF chromatin remodeler Brg1. Molecular and cellular neurosciences 9 24561795
2014 srGAP3 promotes neurite outgrowth of dorsal root ganglion neurons by inactivating RAC1. Asian Pacific journal of tropical medicine 7 25149377
2023 Electroacupuncture inhibits dendritic spine remodeling through the srGAP3-Rac1 signaling pathway in rats with SNL. Biological research 4 37211600

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