Affinage

SRGAP1

SLIT-ROBO Rho GTPase-activating protein 1 · UniProt Q7Z6B7

Length
1085 aa
Mass
124.3 kDa
Annotated
2026-06-10
16 papers in source corpus 14 papers cited in narrative 14 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

SRGAP1 is a Slit-Robo pathway effector that couples Robo1 receptor activation to inactivation of Rho-family GTPases, thereby suppressing cell migration and restraining actin-based protrusions (PMID:20944010, PMID:27923383). Its SH3 domain engages the Robo CC2 and CC3 proline-rich motifs in a defined C-to-N orientation, a recognition mode dictated by a shallow ligand-binding pocket shaped by the conserved Phe-13 residue (PMID:16857672). Downstream of this interaction, the SRGAP1 GAP domain inactivates Cdc42 and Rac1 in a context-dependent manner: in neutrophils and several injury models Slit2-Robo1 signaling drives SRGAP1-mediated Cdc42 inactivation to block chemotaxis and immune-cell infiltration (PMID:20944010, PMID:26550694, PMID:37899442), whereas at lamellipodia SRGAP1 acts as a Rac1-specific GAP that limits Rac1 to permit concomitant RhoA-driven actomyosin contractility and spatially restrict protrusions (PMID:24006490). The N-terminal F-BAR domain confers distinct membrane behavior, antagonizing filopodia formation and dampening plasma membrane dynamics, and can heterodimerize with srGAP2/3 F-BAR domains (PMID:22467852). At epithelial adherens junctions, tyrosine-dephosphorylated cortactin recruits SRGAP1 to antagonize RhoA and downregulate junctional contractility, a pathway co-opted by HGF to promote collective motility (PMID:28983097, PMID:29160905). In podocytes, SRGAP1 localizes to foot processes and limits protrusive Rho GTPase activity to maintain foot-process architecture; podocyte-specific knockout produces an FSGS-like phenotype (PMID:33514561). Human genetic and biochemical studies link SRGAP1 variants to congenital anomalies of the kidney and urinary tract (CAKUT), with mutations altering its GAP activity toward CDC42 and RAC1 (PMID:23539728, PMID:26026792).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Established the structural and biochemical basis for how SRGAP1 physically engages Robo receptors, defining the molecular interface that anchors it to Slit-Robo signaling.

    Evidence X-ray crystallography of the SH3 domain at 1.8 Å plus SPR binding and peptide mutagenesis against Robo CC2/CC3 motifs

    PMID:16857672

    Open questions at the time
    • Does not address GAP catalytic activity or GTPase substrate selection
    • No cellular validation of the binding mode in this study
  2. 2010 Medium

    Showed that SRGAP1 functions as a Slit2/Robo1 effector that inactivates Cdc42 to suppress chemotaxis, and that its expression level dictates the cellular outcome of Slit-Robo signaling.

    Evidence SRGAP1 blocking experiments, Cdc42 activity assay, and migration assays in primary neutrophils versus eosinophils

    PMID:20944010

    Open questions at the time
    • Blocking-based rather than genetic loss-of-function
    • Mechanism of differential expression between leukocyte types not resolved
  3. 2012 Medium

    Distinguished the SRGAP1 F-BAR domain functionally from paralogs, revealing it inhibits rather than promotes membrane protrusions and can heterodimerize with srGAP2/3.

    Evidence Live imaging in COS7 cells and cortical neurons, FRAP, and F-BAR heterodimerization assays

    PMID:22467852

    Open questions at the time
    • F-BAR contribution to in vivo SRGAP1 function not tested
    • Relationship between F-BAR membrane activity and GAP activity unresolved
  4. 2013 High

    Resolved SRGAP1 substrate specificity in migrating cells as Rac1-directed, defining its role in spatially restricting lamellipodia by balancing Rac1 and RhoA.

    Evidence siRNA knockdown, reciprocal GTPase pull-down assays, and live-cell lamellipodia imaging with migration tracking

    PMID:24006490

    Open questions at the time
    • Rac1-specificity here contrasts with Cdc42-directed activity in leukocytes; context-determinants not defined
    • Recruitment mechanism to lamellipodia not fully mapped
  5. 2013 Medium

    Identified disease-associated missense variants in the F-BAR and RhoGAP domains that cripple GAP activity toward CDC42, tying specific residues to catalytic function.

    Evidence In vitro biochemical GTPase inactivation assays with mutant SRGAP1 constructs

    PMID:23539728

    Open questions at the time
    • In vitro assay only; cellular and organismal consequences not tested
    • Single study, single lab
  6. 2015 Medium

    Linked SRGAP1 to kidney development and CAKUT, showing co-expression with ROBO2 in nephron progenitors and gain-of-function GAP variants that excessively inhibit RAC1.

    Evidence Expression/immunohistochemistry in developing kidney plus GTPase activity assays in HEK cells with patient-derived mutants

    PMID:26026792

    Open questions at the time
    • Heterozygous variants; causality not established in an animal model
    • Direction of effect (gain vs loss) differs from other reported variants
  7. 2016 Medium

    Demonstrated SRGAP1 is required downstream of Robo1 for Slit2-mediated Cdc42 inhibition in a brain-injury context, extending the pathway to immune-cell infiltration in vivo.

    Evidence SRGAP1 siRNA knockdown in vivo with Cdc42 activity assay, Western blot, and immunohistochemistry in a rat surgical brain injury model

    PMID:26550694

    Open questions at the time
    • Effects on neuronal versus immune compartments not fully separated
    • GAP activity inferred from pathway readout, not direct structural data
  8. 2016 Medium

    Confirmed the physical SRGAP1-Robo1 interaction and dynamic co-localization in cancer cells, with functional consequences for Cdc42-dependent migration.

    Evidence Reciprocal Co-IP, immunofluorescence, Cdc42 pull-down, and wound-healing migration assays in colorectal cancer cells

    PMID:27923383

    Open questions at the time
    • Single cell-line context
    • Does not address whether Robo1 binding is required for GAP activation in these cells
  9. 2017 High

    Placed SRGAP1 at epithelial adherens junctions as a cortactin-recruited RhoA antagonist that tunes junctional contractility and enables HGF-driven collective motility.

    Evidence Cortactin phospho-mutant expression, SRGAP1 RNAi, RhoA activity assays, junctional tension measurement, and live imaging

    PMID:28983097 PMID:29160905

    Open questions at the time
    • Mechanism by which dephosphorylated cortactin engages SRGAP1 not structurally defined
    • RhoA-directed activity at junctions contrasts with Rac1/Cdc42 specificity elsewhere
  10. 2017 Medium

    Connected SRGAP1 to Wnt/β-catenin signaling in gastric cancer and identified it as a direct miR-340/miR-124 target, indicating post-transcriptional control of its levels.

    Evidence siRNA knockdown, dual luciferase reporter assays, and rescue with SRGAP1 re-expression in gastric cancer cells

    PMID:29234151

    Open questions at the time
    • Molecular link between SRGAP1 and Wnt pathway components not defined
    • GAP activity dependence of the Wnt phenotype untested
  11. 2019 Medium

    Extended the Robo1-SRGAP1 axis to anti-apoptotic, RhoA-directed neuroprotective signaling in neonatal hypoxia-ischemia.

    Evidence SRGAP1 siRNA and decoy Robo1 co-administration with Western blot, immunofluorescence, and TUNEL in a rat neonatal HIE model

    PMID:31356825

    Open questions at the time
    • Direct GAP-substrate relationship in neurons not measured
    • Cell-type origin of the protective effect not isolated
  12. 2021 High

    Established SRGAP1 as essential for podocyte foot-process architecture, showing knockout causes FSGS-like effacement through disinhibition of protrusive Rho GTPases.

    Evidence Podocyte-specific conditional knockout mice, in situ proximity ligation, super-resolution/electron microscopy, CRISPR KO podocytes, and quantitative interaction proteomics

    PMID:33514561

    Open questions at the time
    • Which specific GTPase(s) drive the foot-process phenotype not pinpointed
    • Upstream recruitment signal at foot processes not identified
  13. 2023 Medium

    Reaffirmed the conserved requirement for SRGAP1 in Slit2/Robo1-mediated Cdc42 inhibition and suppression of neuroinflammatory immune infiltration.

    Evidence SRGAP1 siRNA in vivo with Cdc42 activity assay, Western blot, and immunofluorescence in a rat germinal matrix hemorrhage model

    PMID:37899442

    Open questions at the time
    • Confirmatory of prior models rather than mechanistically novel
    • Direct GAP catalysis not assayed in this system

Open questions

Synthesis pass · forward-looking unresolved questions
  • What molecular determinants switch SRGAP1's GAP specificity between Cdc42, Rac1, and RhoA across cell types and subcellular sites remains unresolved.
  • No unified structural or regulatory model reconciling context-dependent substrate selection
  • Recruitment cues directing SRGAP1 to junctions, lamellipodia, and foot processes incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2
Partners
CDC42CTTNRAC1RHOAROBO1ROBO2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structure of the srGAP1 SH3 domain (1.8 Å resolution) revealed that the conserved Phe-13 side chain renders the ligand-binding pocket shallow and narrow. Surface plasmon resonance showed the SH3 domain binds the Robo CC2 and CC3 proline-rich motifs in a C-to-N orientation, with the N-terminal two acidic residues of CC3 required for binding. X-ray crystallography (1.8 Å) + surface plasmon resonance (SPR) + peptide mutagenesis The Journal of biological chemistry High 16857672
2010 In neutrophils, Slit2 activates srGAP1 downstream of Robo1, leading to inactivation of Cdc42 and suppression of SDF-1α-induced chemotaxis. Blockade of srGAP1 binding to Robo1 reversed Slit2-mediated Cdc42 inactivation and migration inhibition. In eosinophils, which express lower levels of srGAP1, Slit2-Robo1 instead recruits PI3K and enhances chemotaxis. srGAP1 blocking experiments, Cdc42 activity assay, cell migration assay, differential expression analysis in primary leukocytes Journal of immunology Medium 20944010
2012 The F-BAR domain of srGAP1 (F-BAR(1)) prevents filopodia formation in cortical neurons and reduces plasma membrane dynamics, in contrast to srGAP2 and srGAP3 F-BAR domains. F-BAR domains of srGAP1, srGAP2, and srGAP3 can heterodimerize and act synergistically on filopodia induction. FRAP showed F-BAR(1) has slower molecular dynamics at the plasma membrane than F-BAR(2). Live imaging in COS7 cells and cortical neurons, FRAP, heterodimerization assay Journal of cell science Medium 22467852
2013 srGAP1 possesses GAP activity specific to Rac1 (not RhoA or Cdc42) and is recruited to lamellipodia in a Rac1-dependent manner. Depletion of srGAP1 overactivates Rac1 and inactivates RhoA, converting random cell motility to directionally persistent migration. srGAP1 limits Rac1 activity to allow concomitant Rac1/RhoA activation, spatially restricting lamellipodia via RhoA-induced actomyosin contractility. siRNA knockdown, GTPase activity assays (pull-down), live-cell imaging of lamellipodia dynamics, cell migration tracking Molecular biology of the cell High 24006490
2013 Two missense variants in the F-BAR domain (Q149H) and RhoGAP domain (R617C) of SRGAP1 severely impaired its ability to inactivate CDC42 in biochemical assays, establishing these residues as functionally critical for GAP activity toward CDC42. Biochemical GTPase inactivation assay with mutant SRGAP1 constructs The Journal of clinical endocrinology and metabolism Medium 23539728
2015 SRGAP1 is expressed in mouse nephrogenic mesenchyme and co-expressed with ROBO2 in SIX2-positive nephron progenitor cells. Two heterozygous SRGAP1 mutations identified in CAKUT families led to augmented inhibition of RAC1 (gain-of-function GAP activity) in cultured human embryonic kidney cells. Immunohistochemistry/expression analysis in developing kidney + small GTPase activity assay in HEK cells with mutant constructs Human genetics Medium 26026792
2015 In a rat surgical brain injury model, recombinant Slit2 reduced peripheral immune cell infiltration and Cdc42 activity via the Robo1-srGAP1 pathway. Knockdown of srGAP1 by siRNA reversed the protective effects of Slit2, confirming srGAP1 is required downstream of Robo1 for Cdc42 inhibition. srGAP1 siRNA knockdown in vivo, Cdc42 activity assay, Western blot, immunohistochemistry in rat model Neurobiology of disease Medium 26550694
2016 Co-immunoprecipitation and immunofluorescence in colorectal cancer cells showed that srGAP1 is a Robo1-interacting protein and co-localizes dynamically with Robo1 after Slit2 treatment. Slit2-Robo1 signaling inhibits Cdc42 activity and cell migration through srGAP1, as confirmed by small GTPase pull-down and migration assays. Co-immunoprecipitation, immunofluorescence, Cdc42 pull-down activity assay, wound-healing migration assay Journal of experimental & clinical cancer research Medium 27923383
2017 Tyrosine-dephosphorylated cortactin recruits SRGAP1 to the epithelial zonula adherens, where SRGAP1 antagonizes RhoA signaling and downregulates junctional contractility. Cortactin phospho-mutants reduced RhoA activity and compromised ZA contractility in a SRGAP1-dependent manner. HGF co-opts this pathway to promote junctional relaxation and collective cell motility. Cortactin phospho-mutant expression, RNAi of SRGAP1, RhoA activity assays, tension measurement at junctions, live imaging Nature communications High 28983097
2017 SRGAP1 is present at subconfluent epithelial junctions and actively suppresses RhoA signaling and contractility. SRGAP1 RNAi in subconfluent Caco-2 cells restored RhoA signaling and junctional contractility to levels seen in confluent monolayers, indicating regulated junctional recruitment of SRGAP1 controls RhoA-dependent contractility during epithelial maturation. SRGAP1 RNAi, RhoA activity assay, junctional tension measurement in Caco-2 epithelial cells Cytoskeleton Medium 29160905
2017 SRGAP1 knockdown in gastric cancer cells inhibited Wnt/β-catenin pathway activity as shown by luciferase reporter assays. SRGAP1 was confirmed as a direct target of miR-340 and miR-124 by dual luciferase reporter and rescue experiments; re-expression of SRGAP1 rescued the anti-cancer effects of miR-340. siRNA knockdown, luciferase reporter assay, rescue experiments with SRGAP1 re-expression Oncogene Medium 29234151
2019 In a neonatal hypoxia-ischemia rat model, recombinant Slit2 reduced neuronal apoptosis via the Robo1-srGAP1 pathway, mediating inhibition of RhoA. Co-administration of decoy Robo1 or srGAP1 siRNA reversed Slit2's neuroprotective effects, placing srGAP1 downstream of Robo1 in Slit2 anti-apoptotic signaling. srGAP1 siRNA, decoy Robo1 co-administration, Western blot, immunofluorescence, TUNEL staining in rat neonatal HIE model Neuropharmacology Medium 31356825
2021 SRGAP1 localizes to podocyte foot processes in vivo (by in situ proximity ligation assay and super-resolution microscopy) and to cellular protrusions in vitro. Podocyte-specific Srgap1 knockout mice developed an FSGS-like phenotype with foot process effacement. SRGAP1-knockout podocytes showed excessive protrusion formation and disinhibition of small Rho GTPases. Quantitative interaction proteomics identified SRGAP1 involvement with protrusive and contractile actin networks. Conditional knockout mice (hNPHS2Cre), in situ proximity ligation assay, super-resolution/electron microscopy, CRISPR/Cas9 KO in cultured podocytes, quantitative interaction proteomics Journal of the American Society of Nephrology High 33514561
2023 In a rat germinal matrix hemorrhage model, recombinant Slit2 suppressed Cdc42-mediated brain infiltration of peripheral immune cells via the Robo1-srGAP1 pathway. srGAP1 siRNA reversed the anti-neuroinflammatory effects of Slit2, confirming srGAP1 is required for Slit2/Robo1-mediated Cdc42 inhibition in this context. srGAP1 siRNA in vivo, Cdc42 activity assay, Western blot, immunofluorescence in rat GMH model Journal of neuroinflammation Medium 37899442

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility. The Journal of clinical endocrinology and metabolism 69 23539728
2012 The F-BAR domains from srGAP1, srGAP2 and srGAP3 regulate membrane deformation differently. Journal of cell science 64 22467852
2010 Slit2 regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation. Journal of immunology (Baltimore, Md. : 1950) 57 20944010
2015 Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Human genetics 53 26026792
2010 The corticofugal neuron-associated genes ROBO1, SRGAP1, and CTIP2 exhibit an anterior to posterior gradient of expression in early fetal human neocortex development. Cerebral cortex (New York, N.Y. : 1991) 44 21060114
2015 Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model. Neurobiology of disease 37 26550694
2017 SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis. Oncogene 34 29234151
2013 srGAP1 regulates lamellipodial dynamics and cell migratory behavior by modulating Rac1 activity. Molecular biology of the cell 33 24006490
2016 srGAP1 mediates the migration inhibition effect of Slit2-Robo1 in colorectal cancer. Journal of experimental & clinical cancer research : CR 31 27923383
2017 Tyrosine dephosphorylated cortactin downregulates contractility at the epithelial zonula adherens through SRGAP1. Nature communications 29 28983097
2021 SRGAP1 Controls Small Rho GTPases To Regulate Podocyte Foot Process Maintenance. Journal of the American Society of Nephrology : JASN 25 33514561
2006 Structural basis of Robo proline-rich motif recognition by the srGAP1 Src homology 3 domain in the Slit-Robo signaling pathway. The Journal of biological chemistry 25 16857672
2019 Recombinant Slit2 attenuates neuronal apoptosis via the Robo1-srGAP1 pathway in a rat model of neonatal HIE. Neuropharmacology 15 31356825
2023 Recombinant Slit2 suppresses neuroinflammation and Cdc42-mediated brain infiltration of peripheral immune cells via Robo1-srGAP1 pathway in a rat model of germinal matrix hemorrhage. Journal of neuroinflammation 12 37899442
2017 Regulated recruitment of SRGAP1 modulates RhoA signaling for contractility during epithelial junction maturation. Cytoskeleton (Hoboken, N.J.) 10 29160905
2023 In silico whole-transcriptome analysis reveals a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 regulatory network related to liver metastasis of colorectal cancer. Heliyon 5 37954397

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