{"gene":"ARHGEF26","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2004,"finding":"SGEF (ARHGEF26) is a RhoG-specific guanine nucleotide exchange factor: recombinant SGEF DH/PH domain exchanged nucleotide on RhoG but not on Rac1 or Rac3 in vitro, and full-length SGEF activated RhoG (but not Rac) in fibroblasts. SGEF stimulated macropinocytosis in a manner requiring a catalytically active DH domain and the full-length protein.","method":"In vitro nucleotide exchange assay (recombinant DH/PH protein), fibroblast overexpression with constitutively active GTPase comparison, dextran uptake assay, scanning electron microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with DH/PH domain plus cellular functional assays with catalytic mutant controls","pmids":["15133129"],"is_preprint":false},{"year":2004,"finding":"SGEF requires its proline-rich N-terminus to generate dorsal membrane ruffles (but not lateral ruffles), and requires a functional SH3 domain to colocalize with filamentous actin at sites of membrane protrusion.","method":"Fibroblast overexpression of domain-deletion/mutation constructs, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion constructs with defined morphological readouts, single lab","pmids":["15133129"],"is_preprint":false},{"year":2003,"finding":"SGEF protein contains DH and PH domains, an N-terminal proline-rich domain, a C-terminal SH3 domain, and two nuclear localization signals. An alternate androgen-responsive promoter drives expression of a truncated isoform (CSGEF) in prostate and liver.","method":"cDNA cloning, sequence analysis, androgen treatment of LNCaP cells with actinomycin D and protein-synthesis inhibitor controls","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with pharmacological controls establishing alternate promoter usage, single lab","pmids":["12697679"],"is_preprint":false},{"year":2013,"finding":"SGEF-deficient mice crossed with ApoE-null mice show reduced atherosclerosis; SGEF-null mouse aortic endothelial cells display decreased RhoG activation around ICAM-1 clusters and reduced endothelial docking structures, establishing that SGEF promotes leukocyte transendothelial migration via RhoG-dependent docking structure formation.","method":"SGEF knockout mouse (crossed with ApoE-null), fluorescent RhoG biosensor, scanning electron microscopy, flow-based bead adhesion assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype combined with live-cell biosensor and ex vivo structural analysis, multiple orthogonal methods","pmids":["23372835"],"is_preprint":false},{"year":2013,"finding":"SGEF delays EGFR trafficking from early to late endosomes, thereby slowing EGFR lysosomal degradation and enhancing EGFR signaling and cell migration in prostate cancer cells; this function is independent of its GEF catalytic activity.","method":"siRNA knockdown, endosomal fractionation/trafficking assays, EGF-induced EGFR degradation assays, cell migration assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with trafficking assays and GEF-independent functional dissection, single lab","pmids":["23661635"],"is_preprint":false},{"year":2016,"finding":"Src kinase tyrosine-phosphorylates SGEF at Y530 within the DH domain, which suppresses SGEF interaction with RhoG, reduces RhoG activation, and inhibits SGEF-mediated cell migration; Y530F mutation blocks this inhibitory effect.","method":"In-cell phosphorylation assays, co-immunoprecipitation, RhoG activity assay, site-directed mutagenesis (Y530F), cell migration assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis identifying specific phosphorylation site combined with functional GTPase activation and migration assays, single lab with multiple orthogonal methods","pmids":["27437949"],"is_preprint":false},{"year":2016,"finding":"SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity; nuclear SGEF complexes with BRCA1 following temozolomide treatment, and SGEF knockdown reduces BRCA1 phosphorylation and sensitizes glioma cells to temozolomide-induced apoptosis.","method":"shRNA knockdown, NF-κB reporter/pathway inhibition, co-immunoprecipitation (SGEF-BRCA1), immunoblot for BRCA1 phosphorylation, apoptosis and colony formation assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying BRCA1 complex plus functional knockdown with multiple readouts, single lab","pmids":["26764186"],"is_preprint":false},{"year":2019,"finding":"SGEF forms a ternary complex with Scribble and Dlg1; SGEF targets to apical junctions in a Scribble-dependent manner and regulates actomyosin contractility and tight junction barrier function (scaffolding activity) as well as E-cadherin adherens junction formation and 3D cyst lumen formation (GEF activity). Polarity establishment is not controlled by SGEF.","method":"Co-immunoprecipitation, confocal localization, siRNA knockdown, 3D cyst assay, TEER measurement, GEF-dead mutant analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-function dissection (GEF vs. scaffold), multiple orthogonal cellular phenotype readouts, single lab with rigorous controls","pmids":["31248911"],"is_preprint":false},{"year":2021,"finding":"ARHGEF26 promotes Salmonella invasion into host epithelial cells in a serovar- and cell-type-dependent manner: it regulates SopB- and SopE-dependent S. Typhi infection in HeLa cells and SopB/SopE2-independent S. Typhimurium infection in polarized MDCK cells. DLG1, an ARHGEF26-associated protein, shows similar serovar-specific knockdown phenotypes. In vivo, Arhgef26 deletion reduces S. Typhimurium burden in enteric fever model and reduces colitis-associated inflammation.","method":"siRNA/shRNA knockdown, genetic deletion mouse model (colitis and enteric fever), bacterial invasion assays in multiple cell types, effector mutant Salmonella strains, IL-8 ELISA","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse knockout plus multiple cell-type knockdown experiments with bacterial mutant epistasis, multiple orthogonal methods","pmids":["34242364"],"is_preprint":false},{"year":2022,"finding":"ARHGEF26 promotes macropinocytosis of VEGFR2 at the cell membrane, is required for VEGF-dependent angiogenesis in ECs, and promotes vessel sprouting ex vivo. Global or EC-specific (but not vascular smooth muscle cell-specific) ARHGEF26 deletion reduces atherosclerosis and enhances plaque stability in mice. A CAD-risk coding variant (p.Val29Leu) results in gain-of-function ARHGEF26 with enhanced proangiogenic signaling and protein interactions.","method":"Quantitative mass spectrometry (variant interactome), EC-specific conditional knockout mice, ex vivo aortic ring sprouting assay, macropinocytosis imaging, atherosclerosis quantification","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout in vivo, quantitative proteomics for variant function, ex vivo functional assay, multiple orthogonal methods","pmids":["34849650"],"is_preprint":false},{"year":2024,"finding":"The Scribble-SGEF-Dlg1 ternary complex is required for ZO-1 protein stability and tight junction permeability; SGEF alone (not Scribble or Dlg1) is required to regulate E-cadherin levels. Loss of SGEF destabilizes the E-cadherin/catenin complex, triggering endocytosis of E-cadherin, β-catenin nuclear signaling, and Slug-mediated transcriptional repression of E-cadherin in a positive feedback loop.","method":"siRNA knockdown of individual complex members, endocytosis assays, β-catenin reporter assay, Slug knockdown rescue, TEER, immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-component knockdown epistasis with pathway dissection and rescue experiments, single lab","pmids":["39350674"],"is_preprint":false},{"year":2025,"finding":"SGEF enhances EGFR stability by inhibiting its ubiquitination, leading to sustained downstream NRF2 activation and ferroptosis inhibition in cardiomyocytes; EGFR inhibitor osimertinib counteracts the cardioprotective effect of SGEF overexpression in pressure-overload cardiac hypertrophy.","method":"AAV9-mediated cardiac overexpression/knockdown, aortic banding mouse model, echocardiography, ubiquitination assay, EGFR inhibitor treatment, oxidative stress and ferroptosis markers","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with pharmacological epistasis, ubiquitination assay, single lab","pmids":["40829739"],"is_preprint":false},{"year":2026,"finding":"ARHGEF26 interacts with and stabilizes the stemness transcription factor SOX2 by inhibiting K48-linked polyubiquitination and proteasomal degradation of SOX2 in glioblastoma stem cells.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), gain/loss-of-function in vitro and in vivo, CD133+/CD15+ cell sorting","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay with functional in vitro/in vivo validation, single lab","pmids":["41936941"],"is_preprint":false}],"current_model":"ARHGEF26/SGEF is a RhoG-specific guanine nucleotide exchange factor (acting through its DH/PH domains) that is negatively regulated by Src-mediated phosphorylation at Y530; it forms a ternary complex with Scribble and Dlg1 to coordinate apical junction assembly and actomyosin contractility at epithelial cell-cell contacts, promotes macropinocytosis (including VEGFR2 internalization driving angiogenesis), facilitates ICAM-1-dependent endothelial docking structure formation for leukocyte transmigration, delays EGFR lysosomal trafficking to enhance EGFR-NRF2 signaling, and additionally performs GEF-independent scaffold functions including stabilization of SOX2 (by blocking K48-linked ubiquitination) and interaction with BRCA1 to modulate DNA damage responses."},"narrative":{"mechanistic_narrative":"ARHGEF26 (SGEF) is a RhoG-specific guanine nucleotide exchange factor that couples membrane remodeling and cell-cell adhesion to processes spanning leukocyte transendothelial migration, angiogenesis, epithelial junction assembly, and pathogen entry [PMID:15133129, PMID:23372835]. Its DH/PH module catalyzes nucleotide exchange selectively on RhoG (not Rac1/Rac3), and this catalytic activity drives macropinocytosis and is required for RhoG-dependent endothelial docking structure formation around ICAM-1 clusters that supports leukocyte transmigration, a function whose loss reduces atherosclerosis in mice [PMID:15133129, PMID:23372835]. GEF activity is gated by Src-mediated phosphorylation at Y530 in the DH domain, which suppresses RhoG binding and activation and inhibits cell migration [PMID:27437949]. In epithelia, SGEF assembles into a ternary complex with Scribble and Dlg1, targets to apical junctions in a Scribble-dependent manner, and uses both its GEF activity (E-cadherin adherens junctions, 3D cyst lumen formation) and a separable scaffolding activity (actomyosin contractility, ZO-1 stability, tight junction barrier function) to coordinate junction integrity [PMID:31248911, PMID:39350674]. Beyond catalysis, ARHGEF26 performs GEF-independent functions: it delays EGFR endosomal-to-lysosomal trafficking and inhibits EGFR ubiquitination to sustain downstream signaling, including NRF2 activation [PMID:23661635, PMID:40829739], and it stabilizes the transcription factor SOX2 by blocking K48-linked polyubiquitination in glioblastoma stem cells [PMID:41936941]. SGEF expression is induced by TWEAK-Fn14/NF-κB signaling, and nuclear SGEF complexes with BRCA1 to modulate DNA damage responses [PMID:26764186]. A CAD-risk coding variant (p.Val29Leu) confers gain-of-function with enhanced proangiogenic signaling, and ARHGEF26 promotes VEGFR2 macropinocytosis required for VEGF-dependent angiogenesis [PMID:34849650].","teleology":[{"year":2003,"claim":"Established the SGEF protein architecture and its regulated expression, defining the domains (DH/PH, proline-rich N-terminus, SH3, NLSs) that would later be assigned distinct functions.","evidence":"cDNA cloning and sequence analysis with androgen-treated LNCaP cells identifying an alternate androgen-responsive promoter driving a truncated isoform","pmids":["12697679"],"confidence":"Medium","gaps":["Did not assign biochemical function to any domain","Functional role of the truncated CSGEF isoform unresolved"]},{"year":2004,"claim":"Defined SGEF as a RhoG-specific GEF, answering what GTPase it activates and linking that catalysis to macropinocytosis and membrane ruffling.","evidence":"In vitro nucleotide exchange with recombinant DH/PH protein, fibroblast overexpression with catalytic mutant and domain-deletion controls, dextran uptake and electron microscopy","pmids":["15133129"],"confidence":"High","gaps":["No upstream regulator of GEF activity identified","Physiological context of macropinocytosis not addressed"]},{"year":2013,"claim":"Demonstrated an in vivo vascular function: SGEF-driven RhoG activation builds endothelial docking structures for leukocyte transmigration, with knockout reducing atherosclerosis.","evidence":"SGEF knockout mouse crossed with ApoE-null, RhoG biosensor, scanning electron microscopy, flow-based bead adhesion","pmids":["23372835"],"confidence":"High","gaps":["Did not resolve how SGEF is recruited to ICAM-1 clusters","Endothelial vs leukocyte contributions to the phenotype not fully separated"]},{"year":2013,"claim":"Revealed a GEF-independent role: SGEF delays EGFR endosomal trafficking to slow degradation and prolong EGFR signaling, separating scaffold from catalytic function.","evidence":"siRNA knockdown, endosomal fractionation/trafficking assays, EGF-induced degradation and migration assays in prostate cancer cells","pmids":["23661635"],"confidence":"Medium","gaps":["Direct EGFR-SGEF interaction and trafficking machinery not defined","Mechanism of trafficking delay unresolved"]},{"year":2016,"claim":"Identified the regulatory switch on SGEF: Src phosphorylation at Y530 in the DH domain suppresses RhoG binding and migration.","evidence":"In-cell phosphorylation, co-IP, RhoG activity assay, Y530F site-directed mutagenesis, migration assay","pmids":["27437949"],"confidence":"High","gaps":["Phosphatase reversing Y530 unknown","Upstream signals activating Src toward SGEF not defined"]},{"year":2016,"claim":"Connected SGEF to DNA damage signaling: NF-κB-induced nuclear SGEF complexes with BRCA1 to modulate temozolomide sensitivity.","evidence":"shRNA knockdown, NF-κB reporter/inhibition, SGEF-BRCA1 co-IP, BRCA1 phospho-immunoblot, apoptosis and colony assays in glioma cells","pmids":["26764186"],"confidence":"Medium","gaps":["Direct vs indirect SGEF-BRCA1 binding not established","Whether GEF activity contributes to this nuclear function unknown"]},{"year":2019,"claim":"Resolved the epithelial junction mechanism: SGEF forms a Scribble-Dlg1 ternary complex and uses GEF activity and scaffolding separately to control adherens/tight junctions and actomyosin contractility.","evidence":"Reciprocal co-IP, confocal localization, siRNA, 3D cyst assay, TEER, GEF-dead mutant dissection","pmids":["31248911"],"confidence":"High","gaps":["Polarity establishment shown to be SGEF-independent, leaving the polarity-junction boundary undefined","GTPase target at junctions not directly confirmed"]},{"year":2021,"claim":"Showed ARHGEF26 is exploited by Salmonella for serovar- and cell-type-specific epithelial invasion, with DLG1 phenocopying it.","evidence":"siRNA/shRNA, deletion mouse colitis/enteric fever models, invasion assays across cell types with effector-mutant strains, IL-8 ELISA","pmids":["34242364"],"confidence":"High","gaps":["Molecular basis of serovar specificity unresolved","Whether GEF or scaffold activity mediates invasion not separated"]},{"year":2022,"claim":"Established ARHGEF26 in VEGFR2 macropinocytosis and angiogenesis, and identified a CAD-risk gain-of-function variant (p.Val29Leu).","evidence":"Quantitative MS variant interactome, EC-specific conditional knockout mice, aortic ring sprouting, macropinocytosis imaging, atherosclerosis quantification","pmids":["34849650"],"confidence":"High","gaps":["Mechanism by which Val29Leu enhances interactions not detailed","Link between macropinocytosis and downstream proangiogenic signaling incompletely mapped"]},{"year":2024,"claim":"Dissected the junction complex further: the Scribble-SGEF-Dlg1 complex maintains ZO-1 stability while SGEF alone controls E-cadherin via an endocytosis/β-catenin/Slug feedback loop.","evidence":"Individual-member siRNA knockdown, endocytosis and β-catenin reporter assays, Slug knockdown rescue, TEER, immunofluorescence","pmids":["39350674"],"confidence":"Medium","gaps":["Direct SGEF-E-cadherin/catenin interaction not shown","Single-lab epistasis without reciprocal validation"]},{"year":2025,"claim":"Extended the EGFR-stabilizing function to cardiomyocytes: SGEF inhibits EGFR ubiquitination to sustain NRF2 and suppress ferroptosis, with osimertinib reversing cardioprotection.","evidence":"AAV9 cardiac overexpression/knockdown, aortic banding model, echocardiography, ubiquitination assay, EGFR inhibitor epistasis, ferroptosis markers","pmids":["40829739"],"confidence":"Medium","gaps":["Direct effect of SGEF on the EGFR ubiquitination machinery not defined","Single-lab finding"]},{"year":2026,"claim":"Identified a second protein-stabilizing scaffold role: ARHGEF26 blocks K48-linked polyubiquitination of SOX2 to maintain glioblastoma stem-cell identity.","evidence":"Co-IP, K48-linkage-specific ubiquitination assay, gain/loss-of-function in vitro and in vivo with CD133+/CD15+ sorting","pmids":["41936941"],"confidence":"Medium","gaps":["E3 ligase antagonized by ARHGEF26 not identified","Whether SGEF directly binds SOX2 or acts through an intermediary unresolved"]},{"year":null,"claim":"How a single RhoG GEF integrates its catalytic activity with multiple GEF-independent protein-stabilization functions (EGFR, SOX2, junctional partners) within one cell remains unresolved.","evidence":"No single study reconciles the catalytic and scaffolding modes or defines what dictates which function dominates in a given tissue","pmids":[],"confidence":"Low","gaps":["No structural model linking DH/PH catalysis to scaffolding surfaces","Mechanism by which SGEF inhibits substrate ubiquitination is undefined","Tissue-specific selection between GEF and scaffold roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9]}],"complexes":["Scribble-SGEF-Dlg1 ternary complex"],"partners":["RHOG","SRC","SCRIB","DLG1","BRCA1","EGFR","SOX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DR7","full_name":"Rho guanine nucleotide exchange factor 26","aliases":["SH3 domain-containing guanine exchange factor"],"length_aa":871,"mass_kda":97.3,"function":"Activates RhoG GTPase by promoting the exchange of GDP by GTP. Required for the formation of membrane ruffles during macropinocytosis. Required for the formation of cup-like structures during trans-endothelial migration of leukocytes. In case of Salmonella enterica infection, activated by SopB, which induces cytoskeleton rearrangements and promotes bacterial entry","subcellular_location":"Cell projection, ruffle","url":"https://www.uniprot.org/uniprotkb/Q96DR7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARHGEF26","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARHGEF26","total_profiled":1310},"omim":[{"mim_id":"617552","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 26; ARHGEF26","url":"https://www.omim.org/entry/617552"},{"mim_id":"179505","title":"RAS HOMOLOG GENE FAMILY, MEMBER G; RHOG","url":"https://www.omim.org/entry/179505"},{"mim_id":"131550","title":"EPIDERMAL GROWTH FACTOR RECEPTOR; EGFR","url":"https://www.omim.org/entry/131550"},{"mim_id":"108355","title":"GROWTH FACTOR RECEPTOR-BOUND PROTEIN 2; GRB2","url":"https://www.omim.org/entry/108355"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARHGEF26"},"hgnc":{"alias_symbol":["DKFZP434D146","SGEF"],"prev_symbol":[]},"alphafold":{"accession":"Q96DR7","domains":[{"cath_id":"1.20.900.10","chopping":"416-629","consensus_level":"high","plddt":89.8499,"start":416,"end":629},{"cath_id":"2.30.29.30","chopping":"658-719_740-776","consensus_level":"high","plddt":86.3909,"start":658,"end":776},{"cath_id":"2.30.30.40","chopping":"792-866","consensus_level":"high","plddt":86.2044,"start":792,"end":866}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DR7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DR7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DR7-F1-predicted_aligned_error_v6.png","plddt_mean":62.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARHGEF26","jax_strain_url":"https://www.jax.org/strain/search?query=ARHGEF26"},"sequence":{"accession":"Q96DR7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DR7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DR7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DR7"}},"corpus_meta":[{"pmid":"15133129","id":"PMC_15133129","title":"SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15133129","citation_count":93,"is_preprint":false},{"pmid":"31248911","id":"PMC_31248911","title":"SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31248911","citation_count":30,"is_preprint":false},{"pmid":"23372835","id":"PMC_23372835","title":"The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23372835","citation_count":28,"is_preprint":false},{"pmid":"12697679","id":"PMC_12697679","title":"Isolation of the novel human guanine nucleotide exchange factor Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF) and of C-terminal SGEF, an N-terminally truncated form of SGEF, the expression of which is regulated by androgen in prostate cancer cells.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/12697679","citation_count":26,"is_preprint":false},{"pmid":"26764186","id":"PMC_26764186","title":"SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/26764186","citation_count":17,"is_preprint":false},{"pmid":"22824926","id":"PMC_22824926","title":"SGEF is overexpressed in prostate cancer and contributes to prostate cancer progression.","date":"2012","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/22824926","citation_count":13,"is_preprint":false},{"pmid":"34242364","id":"PMC_34242364","title":"ARHGEF26 enhances Salmonella invasion and inflammation in cells and mice.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34242364","citation_count":12,"is_preprint":false},{"pmid":"34849650","id":"PMC_34849650","title":"Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling.","date":"2022","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/34849650","citation_count":11,"is_preprint":false},{"pmid":"23661635","id":"PMC_23661635","title":"SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23661635","citation_count":10,"is_preprint":false},{"pmid":"27437949","id":"PMC_27437949","title":"Tyrosine Phosphorylation of SGEF Regulates RhoG Activity and Cell Migration.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27437949","citation_count":9,"is_preprint":false},{"pmid":"39350674","id":"PMC_39350674","title":"The Scribble-SGEF-Dlg1 complex regulates E-cadherin and ZO-1 stability, turnover and transcription in epithelial cells.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/39350674","citation_count":5,"is_preprint":false},{"pmid":"39092889","id":"PMC_39092889","title":"Dexamethasone induces trabecular meshwork cell myofibroblast transdifferentiation through ARHGEF26.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39092889","citation_count":3,"is_preprint":false},{"pmid":"38585765","id":"PMC_38585765","title":"The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38585765","citation_count":0,"is_preprint":false},{"pmid":"40829739","id":"PMC_40829739","title":"SH3-containing guanine nucleotide exchange factor (SGEF) ameliorates pressure overload induced cardiac hypertrophy via enhancing EGFR-NRF2 mediated ferroptosis inhibition.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40829739","citation_count":0,"is_preprint":false},{"pmid":"41936941","id":"PMC_41936941","title":"ARHGEF26 Maintains SOX2 Stability by Inhibiting Ubiquitination to Enhance Glioblastoma Stemness.","date":"2026","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41936941","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9498,"output_tokens":3383,"usd":0.03962,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10957,"output_tokens":4460,"usd":0.083142,"stage2_stop_reason":"end_turn"},"total_usd":0.122762,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"SGEF (ARHGEF26) is a RhoG-specific guanine nucleotide exchange factor: recombinant SGEF DH/PH domain exchanged nucleotide on RhoG but not on Rac1 or Rac3 in vitro, and full-length SGEF activated RhoG (but not Rac) in fibroblasts. SGEF stimulated macropinocytosis in a manner requiring a catalytically active DH domain and the full-length protein.\",\n      \"method\": \"In vitro nucleotide exchange assay (recombinant DH/PH protein), fibroblast overexpression with constitutively active GTPase comparison, dextran uptake assay, scanning electron microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with DH/PH domain plus cellular functional assays with catalytic mutant controls\",\n      \"pmids\": [\"15133129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SGEF requires its proline-rich N-terminus to generate dorsal membrane ruffles (but not lateral ruffles), and requires a functional SH3 domain to colocalize with filamentous actin at sites of membrane protrusion.\",\n      \"method\": \"Fibroblast overexpression of domain-deletion/mutation constructs, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion constructs with defined morphological readouts, single lab\",\n      \"pmids\": [\"15133129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SGEF protein contains DH and PH domains, an N-terminal proline-rich domain, a C-terminal SH3 domain, and two nuclear localization signals. An alternate androgen-responsive promoter drives expression of a truncated isoform (CSGEF) in prostate and liver.\",\n      \"method\": \"cDNA cloning, sequence analysis, androgen treatment of LNCaP cells with actinomycin D and protein-synthesis inhibitor controls\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with pharmacological controls establishing alternate promoter usage, single lab\",\n      \"pmids\": [\"12697679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SGEF-deficient mice crossed with ApoE-null mice show reduced atherosclerosis; SGEF-null mouse aortic endothelial cells display decreased RhoG activation around ICAM-1 clusters and reduced endothelial docking structures, establishing that SGEF promotes leukocyte transendothelial migration via RhoG-dependent docking structure formation.\",\n      \"method\": \"SGEF knockout mouse (crossed with ApoE-null), fluorescent RhoG biosensor, scanning electron microscopy, flow-based bead adhesion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout phenotype combined with live-cell biosensor and ex vivo structural analysis, multiple orthogonal methods\",\n      \"pmids\": [\"23372835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SGEF delays EGFR trafficking from early to late endosomes, thereby slowing EGFR lysosomal degradation and enhancing EGFR signaling and cell migration in prostate cancer cells; this function is independent of its GEF catalytic activity.\",\n      \"method\": \"siRNA knockdown, endosomal fractionation/trafficking assays, EGF-induced EGFR degradation assays, cell migration assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with trafficking assays and GEF-independent functional dissection, single lab\",\n      \"pmids\": [\"23661635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Src kinase tyrosine-phosphorylates SGEF at Y530 within the DH domain, which suppresses SGEF interaction with RhoG, reduces RhoG activation, and inhibits SGEF-mediated cell migration; Y530F mutation blocks this inhibitory effect.\",\n      \"method\": \"In-cell phosphorylation assays, co-immunoprecipitation, RhoG activity assay, site-directed mutagenesis (Y530F), cell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis identifying specific phosphorylation site combined with functional GTPase activation and migration assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27437949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SGEF expression is upregulated by TWEAK-Fn14 signaling via NF-κB activity; nuclear SGEF complexes with BRCA1 following temozolomide treatment, and SGEF knockdown reduces BRCA1 phosphorylation and sensitizes glioma cells to temozolomide-induced apoptosis.\",\n      \"method\": \"shRNA knockdown, NF-κB reporter/pathway inhibition, co-immunoprecipitation (SGEF-BRCA1), immunoblot for BRCA1 phosphorylation, apoptosis and colony formation assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying BRCA1 complex plus functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"26764186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGEF forms a ternary complex with Scribble and Dlg1; SGEF targets to apical junctions in a Scribble-dependent manner and regulates actomyosin contractility and tight junction barrier function (scaffolding activity) as well as E-cadherin adherens junction formation and 3D cyst lumen formation (GEF activity). Polarity establishment is not controlled by SGEF.\",\n      \"method\": \"Co-immunoprecipitation, confocal localization, siRNA knockdown, 3D cyst assay, TEER measurement, GEF-dead mutant analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-function dissection (GEF vs. scaffold), multiple orthogonal cellular phenotype readouts, single lab with rigorous controls\",\n      \"pmids\": [\"31248911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARHGEF26 promotes Salmonella invasion into host epithelial cells in a serovar- and cell-type-dependent manner: it regulates SopB- and SopE-dependent S. Typhi infection in HeLa cells and SopB/SopE2-independent S. Typhimurium infection in polarized MDCK cells. DLG1, an ARHGEF26-associated protein, shows similar serovar-specific knockdown phenotypes. In vivo, Arhgef26 deletion reduces S. Typhimurium burden in enteric fever model and reduces colitis-associated inflammation.\",\n      \"method\": \"siRNA/shRNA knockdown, genetic deletion mouse model (colitis and enteric fever), bacterial invasion assays in multiple cell types, effector mutant Salmonella strains, IL-8 ELISA\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse knockout plus multiple cell-type knockdown experiments with bacterial mutant epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"34242364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARHGEF26 promotes macropinocytosis of VEGFR2 at the cell membrane, is required for VEGF-dependent angiogenesis in ECs, and promotes vessel sprouting ex vivo. Global or EC-specific (but not vascular smooth muscle cell-specific) ARHGEF26 deletion reduces atherosclerosis and enhances plaque stability in mice. A CAD-risk coding variant (p.Val29Leu) results in gain-of-function ARHGEF26 with enhanced proangiogenic signaling and protein interactions.\",\n      \"method\": \"Quantitative mass spectrometry (variant interactome), EC-specific conditional knockout mice, ex vivo aortic ring sprouting assay, macropinocytosis imaging, atherosclerosis quantification\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout in vivo, quantitative proteomics for variant function, ex vivo functional assay, multiple orthogonal methods\",\n      \"pmids\": [\"34849650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Scribble-SGEF-Dlg1 ternary complex is required for ZO-1 protein stability and tight junction permeability; SGEF alone (not Scribble or Dlg1) is required to regulate E-cadherin levels. Loss of SGEF destabilizes the E-cadherin/catenin complex, triggering endocytosis of E-cadherin, β-catenin nuclear signaling, and Slug-mediated transcriptional repression of E-cadherin in a positive feedback loop.\",\n      \"method\": \"siRNA knockdown of individual complex members, endocytosis assays, β-catenin reporter assay, Slug knockdown rescue, TEER, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-component knockdown epistasis with pathway dissection and rescue experiments, single lab\",\n      \"pmids\": [\"39350674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SGEF enhances EGFR stability by inhibiting its ubiquitination, leading to sustained downstream NRF2 activation and ferroptosis inhibition in cardiomyocytes; EGFR inhibitor osimertinib counteracts the cardioprotective effect of SGEF overexpression in pressure-overload cardiac hypertrophy.\",\n      \"method\": \"AAV9-mediated cardiac overexpression/knockdown, aortic banding mouse model, echocardiography, ubiquitination assay, EGFR inhibitor treatment, oxidative stress and ferroptosis markers\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with pharmacological epistasis, ubiquitination assay, single lab\",\n      \"pmids\": [\"40829739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ARHGEF26 interacts with and stabilizes the stemness transcription factor SOX2 by inhibiting K48-linked polyubiquitination and proteasomal degradation of SOX2 in glioblastoma stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), gain/loss-of-function in vitro and in vivo, CD133+/CD15+ cell sorting\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay with functional in vitro/in vivo validation, single lab\",\n      \"pmids\": [\"41936941\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARHGEF26/SGEF is a RhoG-specific guanine nucleotide exchange factor (acting through its DH/PH domains) that is negatively regulated by Src-mediated phosphorylation at Y530; it forms a ternary complex with Scribble and Dlg1 to coordinate apical junction assembly and actomyosin contractility at epithelial cell-cell contacts, promotes macropinocytosis (including VEGFR2 internalization driving angiogenesis), facilitates ICAM-1-dependent endothelial docking structure formation for leukocyte transmigration, delays EGFR lysosomal trafficking to enhance EGFR-NRF2 signaling, and additionally performs GEF-independent scaffold functions including stabilization of SOX2 (by blocking K48-linked ubiquitination) and interaction with BRCA1 to modulate DNA damage responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARHGEF26 (SGEF) is a RhoG-specific guanine nucleotide exchange factor that couples membrane remodeling and cell-cell adhesion to processes spanning leukocyte transendothelial migration, angiogenesis, epithelial junction assembly, and pathogen entry [#0, #3]. Its DH/PH module catalyzes nucleotide exchange selectively on RhoG (not Rac1/Rac3), and this catalytic activity drives macropinocytosis and is required for RhoG-dependent endothelial docking structure formation around ICAM-1 clusters that supports leukocyte transmigration, a function whose loss reduces atherosclerosis in mice [#0, #3]. GEF activity is gated by Src-mediated phosphorylation at Y530 in the DH domain, which suppresses RhoG binding and activation and inhibits cell migration [#5]. In epithelia, SGEF assembles into a ternary complex with Scribble and Dlg1, targets to apical junctions in a Scribble-dependent manner, and uses both its GEF activity (E-cadherin adherens junctions, 3D cyst lumen formation) and a separable scaffolding activity (actomyosin contractility, ZO-1 stability, tight junction barrier function) to coordinate junction integrity [#7, #10]. Beyond catalysis, ARHGEF26 performs GEF-independent functions: it delays EGFR endosomal-to-lysosomal trafficking and inhibits EGFR ubiquitination to sustain downstream signaling, including NRF2 activation [#4, #11], and it stabilizes the transcription factor SOX2 by blocking K48-linked polyubiquitination in glioblastoma stem cells [#12]. SGEF expression is induced by TWEAK-Fn14/NF-\\u03baB signaling, and nuclear SGEF complexes with BRCA1 to modulate DNA damage responses [#6]. A CAD-risk coding variant (p.Val29Leu) confers gain-of-function with enhanced proangiogenic signaling, and ARHGEF26 promotes VEGFR2 macropinocytosis required for VEGF-dependent angiogenesis [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the SGEF protein architecture and its regulated expression, defining the domains (DH/PH, proline-rich N-terminus, SH3, NLSs) that would later be assigned distinct functions.\",\n      \"evidence\": \"cDNA cloning and sequence analysis with androgen-treated LNCaP cells identifying an alternate androgen-responsive promoter driving a truncated isoform\",\n      \"pmids\": [\"12697679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not assign biochemical function to any domain\", \"Functional role of the truncated CSGEF isoform unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined SGEF as a RhoG-specific GEF, answering what GTPase it activates and linking that catalysis to macropinocytosis and membrane ruffling.\",\n      \"evidence\": \"In vitro nucleotide exchange with recombinant DH/PH protein, fibroblast overexpression with catalytic mutant and domain-deletion controls, dextran uptake and electron microscopy\",\n      \"pmids\": [\"15133129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No upstream regulator of GEF activity identified\", \"Physiological context of macropinocytosis not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated an in vivo vascular function: SGEF-driven RhoG activation builds endothelial docking structures for leukocyte transmigration, with knockout reducing atherosclerosis.\",\n      \"evidence\": \"SGEF knockout mouse crossed with ApoE-null, RhoG biosensor, scanning electron microscopy, flow-based bead adhesion\",\n      \"pmids\": [\"23372835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how SGEF is recruited to ICAM-1 clusters\", \"Endothelial vs leukocyte contributions to the phenotype not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a GEF-independent role: SGEF delays EGFR endosomal trafficking to slow degradation and prolong EGFR signaling, separating scaffold from catalytic function.\",\n      \"evidence\": \"siRNA knockdown, endosomal fractionation/trafficking assays, EGF-induced degradation and migration assays in prostate cancer cells\",\n      \"pmids\": [\"23661635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct EGFR-SGEF interaction and trafficking machinery not defined\", \"Mechanism of trafficking delay unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified the regulatory switch on SGEF: Src phosphorylation at Y530 in the DH domain suppresses RhoG binding and migration.\",\n      \"evidence\": \"In-cell phosphorylation, co-IP, RhoG activity assay, Y530F site-directed mutagenesis, migration assay\",\n      \"pmids\": [\"27437949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing Y530 unknown\", \"Upstream signals activating Src toward SGEF not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SGEF to DNA damage signaling: NF-\\u03baB-induced nuclear SGEF complexes with BRCA1 to modulate temozolomide sensitivity.\",\n      \"evidence\": \"shRNA knockdown, NF-\\u03baB reporter/inhibition, SGEF-BRCA1 co-IP, BRCA1 phospho-immunoblot, apoptosis and colony assays in glioma cells\",\n      \"pmids\": [\"26764186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect SGEF-BRCA1 binding not established\", \"Whether GEF activity contributes to this nuclear function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the epithelial junction mechanism: SGEF forms a Scribble-Dlg1 ternary complex and uses GEF activity and scaffolding separately to control adherens/tight junctions and actomyosin contractility.\",\n      \"evidence\": \"Reciprocal co-IP, confocal localization, siRNA, 3D cyst assay, TEER, GEF-dead mutant dissection\",\n      \"pmids\": [\"31248911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Polarity establishment shown to be SGEF-independent, leaving the polarity-junction boundary undefined\", \"GTPase target at junctions not directly confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ARHGEF26 is exploited by Salmonella for serovar- and cell-type-specific epithelial invasion, with DLG1 phenocopying it.\",\n      \"evidence\": \"siRNA/shRNA, deletion mouse colitis/enteric fever models, invasion assays across cell types with effector-mutant strains, IL-8 ELISA\",\n      \"pmids\": [\"34242364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of serovar specificity unresolved\", \"Whether GEF or scaffold activity mediates invasion not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ARHGEF26 in VEGFR2 macropinocytosis and angiogenesis, and identified a CAD-risk gain-of-function variant (p.Val29Leu).\",\n      \"evidence\": \"Quantitative MS variant interactome, EC-specific conditional knockout mice, aortic ring sprouting, macropinocytosis imaging, atherosclerosis quantification\",\n      \"pmids\": [\"34849650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Val29Leu enhances interactions not detailed\", \"Link between macropinocytosis and downstream proangiogenic signaling incompletely mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected the junction complex further: the Scribble-SGEF-Dlg1 complex maintains ZO-1 stability while SGEF alone controls E-cadherin via an endocytosis/\\u03b2-catenin/Slug feedback loop.\",\n      \"evidence\": \"Individual-member siRNA knockdown, endocytosis and \\u03b2-catenin reporter assays, Slug knockdown rescue, TEER, immunofluorescence\",\n      \"pmids\": [\"39350674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SGEF-E-cadherin/catenin interaction not shown\", \"Single-lab epistasis without reciprocal validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the EGFR-stabilizing function to cardiomyocytes: SGEF inhibits EGFR ubiquitination to sustain NRF2 and suppress ferroptosis, with osimertinib reversing cardioprotection.\",\n      \"evidence\": \"AAV9 cardiac overexpression/knockdown, aortic banding model, echocardiography, ubiquitination assay, EGFR inhibitor epistasis, ferroptosis markers\",\n      \"pmids\": [\"40829739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of SGEF on the EGFR ubiquitination machinery not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a second protein-stabilizing scaffold role: ARHGEF26 blocks K48-linked polyubiquitination of SOX2 to maintain glioblastoma stem-cell identity.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assay, gain/loss-of-function in vitro and in vivo with CD133+/CD15+ sorting\",\n      \"pmids\": [\"41936941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase antagonized by ARHGEF26 not identified\", \"Whether SGEF directly binds SOX2 or acts through an intermediary unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single RhoG GEF integrates its catalytic activity with multiple GEF-independent protein-stabilization functions (EGFR, SOX2, junctional partners) within one cell remains unresolved.\",\n      \"evidence\": \"No single study reconciles the catalytic and scaffolding modes or defines what dictates which function dominates in a given tissue\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking DH/PH catalysis to scaffolding surfaces\", \"Mechanism by which SGEF inhibits substrate ubiquitination is undefined\", \"Tissue-specific selection between GEF and scaffold roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005085\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"Scribble-SGEF-Dlg1 ternary complex\"\n    ],\n    \"partners\": [\n      \"RHOG\",\n      \"SRC\",\n      \"SCRIB\",\n      \"DLG1\",\n      \"BRCA1\",\n      \"EGFR\",\n      \"SOX2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}