{"gene":"SRGAP1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"X-ray crystallography (1.8 Å) + surface plasmon resonance (SPR) + peptide mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SPR binding assay with mutagenesis, multiple orthogonal methods in one rigorous study","pmids":["16857672"],"is_preprint":false},{"year":2010,"finding":"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.","method":"srGAP1 blocking experiments, Cdc42 activity assay, cell migration assay, differential expression analysis in primary leukocytes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking experiments with activity assays and migration readout, single lab with two orthogonal methods","pmids":["20944010"],"is_preprint":false},{"year":2012,"finding":"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).","method":"Live imaging in COS7 cells and cortical neurons, FRAP, heterodimerization assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus FRAP plus heterodimerization, single lab, multiple orthogonal methods","pmids":["22467852"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA knockdown, GTPase activity assays (pull-down), live-cell imaging of lamellipodia dynamics, cell migration tracking","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal GTPase activity assays plus live imaging plus KD with defined migratory phenotype, multiple orthogonal methods","pmids":["24006490"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Biochemical GTPase inactivation assay with mutant SRGAP1 constructs","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical mutagenesis assay, single study, single lab","pmids":["23539728"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Immunohistochemistry/expression analysis in developing kidney + small GTPase activity assay in HEK cells with mutant constructs","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTPase activity assay in cultured cells plus in vivo localization, single lab, two orthogonal methods","pmids":["26026792"],"is_preprint":false},{"year":2015,"finding":"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.","method":"srGAP1 siRNA knockdown in vivo, Cdc42 activity assay, Western blot, immunohistochemistry in rat model","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with activity assay readout in vivo, single lab, two orthogonal methods","pmids":["26550694"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence, Cdc42 pull-down activity assay, wound-healing migration assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional GTPase and migration assays, single lab, multiple orthogonal methods","pmids":["27923383"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Cortactin phospho-mutant expression, RNAi of SRGAP1, RhoA activity assays, tension measurement at junctions, live imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (phospho-mutants, RNAi, RhoA activity assay, tension measurement) with defined cellular phenotype, mechanistic pathway placement","pmids":["28983097"],"is_preprint":false},{"year":2017,"finding":"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.","method":"SRGAP1 RNAi, RhoA activity assay, junctional tension measurement in Caco-2 epithelial cells","journal":"Cytoskeleton","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with RhoA activity and tension assays, single lab, two orthogonal methods","pmids":["29160905"],"is_preprint":false},{"year":2017,"finding":"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.","method":"siRNA knockdown, luciferase reporter assay, rescue experiments with SRGAP1 re-expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter with rescue experiment confirming direct miRNA targeting and pathway activation, single lab","pmids":["29234151"],"is_preprint":false},{"year":2019,"finding":"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.","method":"srGAP1 siRNA, decoy Robo1 co-administration, Western blot, immunofluorescence, TUNEL staining in rat neonatal HIE model","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with multiple readouts in vivo, single lab, consistent with prior studies","pmids":["31356825"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional knockout mice (hNPHS2Cre), in situ proximity ligation assay, super-resolution/electron microscopy, CRISPR/Cas9 KO in cultured podocytes, quantitative interaction proteomics","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — conditional KO with defined phenotype, super-resolution localization, proteomics, CRISPR KO in vitro, multiple orthogonal methods in one study","pmids":["33514561"],"is_preprint":false},{"year":2023,"finding":"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.","method":"srGAP1 siRNA in vivo, Cdc42 activity assay, Western blot, immunofluorescence in rat GMH model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with Cdc42 activity assay in vivo, single lab, consistent with multiple prior studies","pmids":["37899442"],"is_preprint":false}],"current_model":"SRGAP1 is a Slit-Robo pathway effector that functions as a RhoGAP downstream of Robo1: its SH3 domain binds Robo1 CC2/CC3 proline-rich motifs (structurally defined at 1.8 Å), and its GAP domain inactivates Cdc42 and Rac1 (with substrate specificity depending on context) to suppress cell migration, regulate lamellipodia dynamics, and control actin-based protrusions; at epithelial adherens junctions, dephosphorylated cortactin recruits SRGAP1 to antagonize RhoA and downregulate contractility, while in podocytes SRGAP1 localizes to foot processes where it limits protrusive Rho GTPase activity to maintain foot-process architecture."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2006,"claim":"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","pmids":["16857672"],"confidence":"High","gaps":["Does not address GAP catalytic activity or GTPase substrate selection","No cellular validation of the binding mode in this study"]},{"year":2010,"claim":"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","pmids":["20944010"],"confidence":"Medium","gaps":["Blocking-based rather than genetic loss-of-function","Mechanism of differential expression between leukocyte types not resolved"]},{"year":2012,"claim":"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","pmids":["22467852"],"confidence":"Medium","gaps":["F-BAR contribution to in vivo SRGAP1 function not tested","Relationship between F-BAR membrane activity and GAP activity unresolved"]},{"year":2013,"claim":"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","pmids":["24006490"],"confidence":"High","gaps":["Rac1-specificity here contrasts with Cdc42-directed activity in leukocytes; context-determinants not defined","Recruitment mechanism to lamellipodia not fully mapped"]},{"year":2013,"claim":"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","pmids":["23539728"],"confidence":"Medium","gaps":["In vitro assay only; cellular and organismal consequences not tested","Single study, single lab"]},{"year":2015,"claim":"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","pmids":["26026792"],"confidence":"Medium","gaps":["Heterozygous variants; causality not established in an animal model","Direction of effect (gain vs loss) differs from other reported variants"]},{"year":2016,"claim":"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","pmids":["26550694"],"confidence":"Medium","gaps":["Effects on neuronal versus immune compartments not fully separated","GAP activity inferred from pathway readout, not direct structural data"]},{"year":2016,"claim":"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","pmids":["27923383"],"confidence":"Medium","gaps":["Single cell-line context","Does not address whether Robo1 binding is required for GAP activation in these cells"]},{"year":2017,"claim":"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","pmids":["28983097","29160905"],"confidence":"High","gaps":["Mechanism by which dephosphorylated cortactin engages SRGAP1 not structurally defined","RhoA-directed activity at junctions contrasts with Rac1/Cdc42 specificity elsewhere"]},{"year":2017,"claim":"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","pmids":["29234151"],"confidence":"Medium","gaps":["Molecular link between SRGAP1 and Wnt pathway components not defined","GAP activity dependence of the Wnt phenotype untested"]},{"year":2019,"claim":"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","pmids":["31356825"],"confidence":"Medium","gaps":["Direct GAP-substrate relationship in neurons not measured","Cell-type origin of the protective effect not isolated"]},{"year":2021,"claim":"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","pmids":["33514561"],"confidence":"High","gaps":["Which specific GTPase(s) drive the foot-process phenotype not pinpointed","Upstream recruitment signal at foot processes not identified"]},{"year":2023,"claim":"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","pmids":["37899442"],"confidence":"Medium","gaps":["Confirmatory of prior models rather than mechanistically novel","Direct GAP catalysis not assayed in this system"]},{"year":null,"claim":"What molecular determinants switch SRGAP1's GAP specificity between Cdc42, Rac1, and RhoA across cell types and subcellular sites remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,4,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6,13]}],"complexes":[],"partners":["ROBO1","ROBO2","CDC42","RAC1","RHOA","CTTN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z6B7","full_name":"SLIT-ROBO Rho GTPase-activating protein 1","aliases":["Rho GTPase-activating protein 13"],"length_aa":1085,"mass_kda":124.3,"function":"GTPase-activating protein for RhoA and Cdc42 small GTPases. Together with CDC42 seems to be involved in the pathway mediating the repulsive signaling of Robo and Slit proteins in neuronal migration. SLIT2, probably through interaction with ROBO1, increases the interaction of SRGAP1 with ROBO1 and inactivates CDC42","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7Z6B7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SRGAP1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SRGAP1","total_profiled":1310},"omim":[{"mim_id":"606525","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 3; SRGAP3","url":"https://www.omim.org/entry/606525"},{"mim_id":"606524","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 2; SRGAP2","url":"https://www.omim.org/entry/606524"},{"mim_id":"606523","title":"SLIT-ROBO RHO GTPase-ACTIVATING PROTEIN 1; SRGAP1","url":"https://www.omim.org/entry/606523"},{"mim_id":"603746","title":"SLIT GUIDANCE LIGAND 2; SLIT2","url":"https://www.omim.org/entry/603746"},{"mim_id":"188550","title":"THYROID CANCER, NONMEDULLARY, 1; NMTC1","url":"https://www.omim.org/entry/188550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SRGAP1"},"hgnc":{"alias_symbol":["KIAA1304","ARHGAP13"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z6B7","domains":[{"cath_id":"1.20.1270.60","chopping":"17-193_211-287","consensus_level":"medium","plddt":91.717,"start":17,"end":287},{"cath_id":"1.10.555.10","chopping":"507-692","consensus_level":"high","plddt":92.1283,"start":507,"end":692},{"cath_id":"2.30.30.40","chopping":"745-798","consensus_level":"high","plddt":91.0926,"start":745,"end":798},{"cath_id":"1.10.287","chopping":"348-393_422-469","consensus_level":"medium","plddt":93.0124,"start":348,"end":469}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6B7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6B7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z6B7-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SRGAP1","jax_strain_url":"https://www.jax.org/strain/search?query=SRGAP1"},"sequence":{"accession":"Q7Z6B7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z6B7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z6B7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z6B7"}},"corpus_meta":[{"pmid":"23539728","id":"PMC_23539728","title":"SRGAP1 is a candidate gene for papillary thyroid carcinoma susceptibility.","date":"2013","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23539728","citation_count":69,"is_preprint":false},{"pmid":"22467852","id":"PMC_22467852","title":"The F-BAR domains from srGAP1, srGAP2 and srGAP3 regulate membrane deformation differently.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22467852","citation_count":64,"is_preprint":false},{"pmid":"20944010","id":"PMC_20944010","title":"Slit2 regulates attractive eosinophil and repulsive neutrophil chemotaxis through differential srGAP1 expression during lung inflammation.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20944010","citation_count":57,"is_preprint":false},{"pmid":"26026792","id":"PMC_26026792","title":"Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.","date":"2015","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26026792","citation_count":53,"is_preprint":false},{"pmid":"21060114","id":"PMC_21060114","title":"The corticofugal neuron-associated genes ROBO1, SRGAP1, and CTIP2 exhibit an anterior to posterior gradient of expression in early fetal human neocortex development.","date":"2010","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/21060114","citation_count":44,"is_preprint":false},{"pmid":"26550694","id":"PMC_26550694","title":"Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model.","date":"2015","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/26550694","citation_count":37,"is_preprint":false},{"pmid":"29234151","id":"PMC_29234151","title":"SRGAP1, a crucial target of miR-340 and miR-124, 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HIE.","date":"2019","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31356825","citation_count":15,"is_preprint":false},{"pmid":"37899442","id":"PMC_37899442","title":"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.","date":"2023","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37899442","citation_count":12,"is_preprint":false},{"pmid":"29160905","id":"PMC_29160905","title":"Regulated recruitment of SRGAP1 modulates RhoA signaling for contractility during epithelial junction maturation.","date":"2017","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/29160905","citation_count":10,"is_preprint":false},{"pmid":"37954397","id":"PMC_37954397","title":"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.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37954397","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11068,"output_tokens":3786,"usd":0.044997,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11347,"output_tokens":4265,"usd":0.08168,"stage2_stop_reason":"end_turn"},"total_usd":0.126677,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (1.8 Å) + surface plasmon resonance (SPR) + peptide mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SPR binding assay with mutagenesis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"16857672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"srGAP1 blocking experiments, Cdc42 activity assay, cell migration assay, differential expression analysis in primary leukocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking experiments with activity assays and migration readout, single lab with two orthogonal methods\",\n      \"pmids\": [\"20944010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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).\",\n      \"method\": \"Live imaging in COS7 cells and cortical neurons, FRAP, heterodimerization assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus FRAP plus heterodimerization, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22467852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, GTPase activity assays (pull-down), live-cell imaging of lamellipodia dynamics, cell migration tracking\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal GTPase activity assays plus live imaging plus KD with defined migratory phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"24006490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical GTPase inactivation assay with mutant SRGAP1 constructs\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical mutagenesis assay, single study, single lab\",\n      \"pmids\": [\"23539728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry/expression analysis in developing kidney + small GTPase activity assay in HEK cells with mutant constructs\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTPase activity assay in cultured cells plus in vivo localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"26026792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"srGAP1 siRNA knockdown in vivo, Cdc42 activity assay, Western blot, immunohistochemistry in rat model\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with activity assay readout in vivo, single lab, two orthogonal methods\",\n      \"pmids\": [\"26550694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Cdc42 pull-down activity assay, wound-healing migration assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional GTPase and migration assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27923383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Cortactin phospho-mutant expression, RNAi of SRGAP1, RhoA activity assays, tension measurement at junctions, live imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (phospho-mutants, RNAi, RhoA activity assay, tension measurement) with defined cellular phenotype, mechanistic pathway placement\",\n      \"pmids\": [\"28983097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"SRGAP1 RNAi, RhoA activity assay, junctional tension measurement in Caco-2 epithelial cells\",\n      \"journal\": \"Cytoskeleton\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with RhoA activity and tension assays, single lab, two orthogonal methods\",\n      \"pmids\": [\"29160905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, rescue experiments with SRGAP1 re-expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter with rescue experiment confirming direct miRNA targeting and pathway activation, single lab\",\n      \"pmids\": [\"29234151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"srGAP1 siRNA, decoy Robo1 co-administration, Western blot, immunofluorescence, TUNEL staining in rat neonatal HIE model\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with multiple readouts in vivo, single lab, consistent with prior studies\",\n      \"pmids\": [\"31356825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice (hNPHS2Cre), in situ proximity ligation assay, super-resolution/electron microscopy, CRISPR/Cas9 KO in cultured podocytes, quantitative interaction proteomics\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — conditional KO with defined phenotype, super-resolution localization, proteomics, CRISPR KO in vitro, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33514561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"srGAP1 siRNA in vivo, Cdc42 activity assay, Western blot, immunofluorescence in rat GMH model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with Cdc42 activity assay in vivo, single lab, consistent with multiple prior studies\",\n      \"pmids\": [\"37899442\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SRGAP1 is a Slit-Robo pathway effector that functions as a RhoGAP downstream of Robo1: its SH3 domain binds Robo1 CC2/CC3 proline-rich motifs (structurally defined at 1.8 Å), and its GAP domain inactivates Cdc42 and Rac1 (with substrate specificity depending on context) to suppress cell migration, regulate lamellipodia dynamics, and control actin-based protrusions; at epithelial adherens junctions, dephosphorylated cortactin recruits SRGAP1 to antagonize RhoA and downregulate contractility, while in podocytes SRGAP1 localizes to foot processes where it limits protrusive Rho GTPase activity to maintain foot-process architecture.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1, #7]. 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 [#0]. 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 [#1, #6, #13], whereas at lamellipodia SRGAP1 acts as a Rac1-specific GAP that limits Rac1 to permit concomitant RhoA-driven actomyosin contractility and spatially restrict protrusions [#3]. 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 [#2]. 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 [#8, #9]. 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 [#12]. 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 [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the structural and biochemical basis for how SRGAP1 physically engages Robo receptors, defining the molecular interface that anchors it to Slit-Robo signaling.\",\n      \"evidence\": \"X-ray crystallography of the SH3 domain at 1.8 Å plus SPR binding and peptide mutagenesis against Robo CC2/CC3 motifs\",\n      \"pmids\": [\"16857672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address GAP catalytic activity or GTPase substrate selection\", \"No cellular validation of the binding mode in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"SRGAP1 blocking experiments, Cdc42 activity assay, and migration assays in primary neutrophils versus eosinophils\",\n      \"pmids\": [\"20944010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Blocking-based rather than genetic loss-of-function\", \"Mechanism of differential expression between leukocyte types not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Distinguished the SRGAP1 F-BAR domain functionally from paralogs, revealing it inhibits rather than promotes membrane protrusions and can heterodimerize with srGAP2/3.\",\n      \"evidence\": \"Live imaging in COS7 cells and cortical neurons, FRAP, and F-BAR heterodimerization assays\",\n      \"pmids\": [\"22467852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"F-BAR contribution to in vivo SRGAP1 function not tested\", \"Relationship between F-BAR membrane activity and GAP activity unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved SRGAP1 substrate specificity in migrating cells as Rac1-directed, defining its role in spatially restricting lamellipodia by balancing Rac1 and RhoA.\",\n      \"evidence\": \"siRNA knockdown, reciprocal GTPase pull-down assays, and live-cell lamellipodia imaging with migration tracking\",\n      \"pmids\": [\"24006490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rac1-specificity here contrasts with Cdc42-directed activity in leukocytes; context-determinants not defined\", \"Recruitment mechanism to lamellipodia not fully mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified disease-associated missense variants in the F-BAR and RhoGAP domains that cripple GAP activity toward CDC42, tying specific residues to catalytic function.\",\n      \"evidence\": \"In vitro biochemical GTPase inactivation assays with mutant SRGAP1 constructs\",\n      \"pmids\": [\"23539728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro assay only; cellular and organismal consequences not tested\", \"Single study, single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Expression/immunohistochemistry in developing kidney plus GTPase activity assays in HEK cells with patient-derived mutants\",\n      \"pmids\": [\"26026792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterozygous variants; causality not established in an animal model\", \"Direction of effect (gain vs loss) differs from other reported variants\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"SRGAP1 siRNA knockdown in vivo with Cdc42 activity assay, Western blot, and immunohistochemistry in a rat surgical brain injury model\",\n      \"pmids\": [\"26550694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effects on neuronal versus immune compartments not fully separated\", \"GAP activity inferred from pathway readout, not direct structural data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the physical SRGAP1-Robo1 interaction and dynamic co-localization in cancer cells, with functional consequences for Cdc42-dependent migration.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence, Cdc42 pull-down, and wound-healing migration assays in colorectal cancer cells\",\n      \"pmids\": [\"27923383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line context\", \"Does not address whether Robo1 binding is required for GAP activation in these cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed SRGAP1 at epithelial adherens junctions as a cortactin-recruited RhoA antagonist that tunes junctional contractility and enables HGF-driven collective motility.\",\n      \"evidence\": \"Cortactin phospho-mutant expression, SRGAP1 RNAi, RhoA activity assays, junctional tension measurement, and live imaging\",\n      \"pmids\": [\"28983097\", \"29160905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which dephosphorylated cortactin engages SRGAP1 not structurally defined\", \"RhoA-directed activity at junctions contrasts with Rac1/Cdc42 specificity elsewhere\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown, dual luciferase reporter assays, and rescue with SRGAP1 re-expression in gastric cancer cells\",\n      \"pmids\": [\"29234151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between SRGAP1 and Wnt pathway components not defined\", \"GAP activity dependence of the Wnt phenotype untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the Robo1-SRGAP1 axis to anti-apoptotic, RhoA-directed neuroprotective signaling in neonatal hypoxia-ischemia.\",\n      \"evidence\": \"SRGAP1 siRNA and decoy Robo1 co-administration with Western blot, immunofluorescence, and TUNEL in a rat neonatal HIE model\",\n      \"pmids\": [\"31356825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAP-substrate relationship in neurons not measured\", \"Cell-type origin of the protective effect not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SRGAP1 as essential for podocyte foot-process architecture, showing knockout causes FSGS-like effacement through disinhibition of protrusive Rho GTPases.\",\n      \"evidence\": \"Podocyte-specific conditional knockout mice, in situ proximity ligation, super-resolution/electron microscopy, CRISPR KO podocytes, and quantitative interaction proteomics\",\n      \"pmids\": [\"33514561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific GTPase(s) drive the foot-process phenotype not pinpointed\", \"Upstream recruitment signal at foot processes not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reaffirmed the conserved requirement for SRGAP1 in Slit2/Robo1-mediated Cdc42 inhibition and suppression of neuroinflammatory immune infiltration.\",\n      \"evidence\": \"SRGAP1 siRNA in vivo with Cdc42 activity assay, Western blot, and immunofluorescence in a rat germinal matrix hemorrhage model\",\n      \"pmids\": [\"37899442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Confirmatory of prior models rather than mechanistically novel\", \"Direct GAP catalysis not assayed in this system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What molecular determinants switch SRGAP1's GAP specificity between Cdc42, Rac1, and RhoA across cell types and subcellular sites remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural or regulatory model reconciling context-dependent substrate selection\", \"Recruitment cues directing SRGAP1 to junctions, lamellipodia, and foot processes incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 4, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ROBO1\",\n      \"ROBO2\",\n      \"CDC42\",\n      \"RAC1\",\n      \"RHOA\",\n      \"CTTN\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}