Affinage

ARHGEF26

Rho guanine nucleotide exchange factor 26 · UniProt Q96DR7

Length
871 aa
Mass
97.3 kDa
Annotated
2026-06-09
15 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 Medium

    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

    PMID:12697679

    Open questions at the time
    • Did not assign biochemical function to any domain
    • Functional role of the truncated CSGEF isoform unresolved
  2. 2004 High

    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

    PMID:15133129

    Open questions at the time
    • No upstream regulator of GEF activity identified
    • Physiological context of macropinocytosis not addressed
  3. 2013 High

    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

    PMID:23372835

    Open questions at the time
    • Did not resolve how SGEF is recruited to ICAM-1 clusters
    • Endothelial vs leukocyte contributions to the phenotype not fully separated
  4. 2013 Medium

    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

    PMID:23661635

    Open questions at the time
    • Direct EGFR-SGEF interaction and trafficking machinery not defined
    • Mechanism of trafficking delay unresolved
  5. 2016 High

    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

    PMID:27437949

    Open questions at the time
    • Phosphatase reversing Y530 unknown
    • Upstream signals activating Src toward SGEF not defined
  6. 2016 Medium

    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

    PMID:26764186

    Open questions at the time
    • Direct vs indirect SGEF-BRCA1 binding not established
    • Whether GEF activity contributes to this nuclear function unknown
  7. 2019 High

    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

    PMID:31248911

    Open questions at the time
    • Polarity establishment shown to be SGEF-independent, leaving the polarity-junction boundary undefined
    • GTPase target at junctions not directly confirmed
  8. 2021 High

    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

    PMID:34242364

    Open questions at the time
    • Molecular basis of serovar specificity unresolved
    • Whether GEF or scaffold activity mediates invasion not separated
  9. 2022 High

    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

    PMID:34849650

    Open questions at the time
    • Mechanism by which Val29Leu enhances interactions not detailed
    • Link between macropinocytosis and downstream proangiogenic signaling incompletely mapped
  10. 2024 Medium

    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

    PMID:39350674

    Open questions at the time
    • Direct SGEF-E-cadherin/catenin interaction not shown
    • Single-lab epistasis without reciprocal validation
  11. 2025 Medium

    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

    PMID:40829739

    Open questions at the time
    • Direct effect of SGEF on the EGFR ubiquitination machinery not defined
    • Single-lab finding
  12. 2026 Medium

    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

    PMID:41936941

    Open questions at the time
    • E3 ligase antagonized by ARHGEF26 not identified
    • Whether SGEF directly binds SOX2 or acts through an intermediary unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005768 endosome 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
BRCA1DLG1EGFRRHOGSCRIBSOX2SRC
Complex memberships
Scribble-SGEF-Dlg1 ternary complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. In vitro nucleotide exchange assay (recombinant DH/PH protein), fibroblast overexpression with constitutively active GTPase comparison, dextran uptake assay, scanning electron microscopy Molecular biology of the cell High 15133129
2004 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. Fibroblast overexpression of domain-deletion/mutation constructs, fluorescence microscopy Molecular biology of the cell Medium 15133129
2003 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. cDNA cloning, sequence analysis, androgen treatment of LNCaP cells with actinomycin D and protein-synthesis inhibitor controls Endocrinology Medium 12697679
2013 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. SGEF knockout mouse (crossed with ApoE-null), fluorescent RhoG biosensor, scanning electron microscopy, flow-based bead adhesion assay PloS one High 23372835
2013 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. siRNA knockdown, endosomal fractionation/trafficking assays, EGF-induced EGFR degradation assays, cell migration assay Carcinogenesis Medium 23661635
2016 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. In-cell phosphorylation assays, co-immunoprecipitation, RhoG activity assay, site-directed mutagenesis (Y530F), cell migration assay PloS one High 27437949
2016 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. shRNA knockdown, NF-κB reporter/pathway inhibition, co-immunoprecipitation (SGEF-BRCA1), immunoblot for BRCA1 phosphorylation, apoptosis and colony formation assays Molecular cancer research : MCR Medium 26764186
2019 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. Co-immunoprecipitation, confocal localization, siRNA knockdown, 3D cyst assay, TEER measurement, GEF-dead mutant analysis The Journal of cell biology High 31248911
2021 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. 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 PLoS pathogens High 34242364
2022 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. Quantitative mass spectrometry (variant interactome), EC-specific conditional knockout mice, ex vivo aortic ring sprouting assay, macropinocytosis imaging, atherosclerosis quantification Cardiovascular research High 34849650
2024 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. siRNA knockdown of individual complex members, endocytosis assays, β-catenin reporter assay, Slug knockdown rescue, TEER, immunofluorescence Journal of cell science Medium 39350674
2025 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. AAV9-mediated cardiac overexpression/knockdown, aortic banding mouse model, echocardiography, ubiquitination assay, EGFR inhibitor treatment, oxidative stress and ferroptosis markers Cellular signalling Medium 40829739
2026 ARHGEF26 interacts with and stabilizes the stemness transcription factor SOX2 by inhibiting K48-linked polyubiquitination and proteasomal degradation of SOX2 in glioblastoma stem cells. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), gain/loss-of-function in vitro and in vivo, CD133+/CD15+ cell sorting Laboratory investigation Medium 41936941

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Molecular biology of the cell 93 15133129
2019 SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility. The Journal of cell biology 30 31248911
2013 The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. PloS one 28 23372835
2003 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. Endocrinology 26 12697679
2016 SGEF Is Regulated via TWEAK/Fn14/NF-κB Signaling and Promotes Survival by Modulation of the DNA Repair Response to Temozolomide. Molecular cancer research : MCR 17 26764186
2012 SGEF is overexpressed in prostate cancer and contributes to prostate cancer progression. Oncology reports 13 22824926
2021 ARHGEF26 enhances Salmonella invasion and inflammation in cells and mice. PLoS pathogens 12 34242364
2022 Endothelial ARHGEF26 is an angiogenic factor promoting VEGF signalling. Cardiovascular research 11 34849650
2013 SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes. Carcinogenesis 10 23661635
2016 Tyrosine Phosphorylation of SGEF Regulates RhoG Activity and Cell Migration. PloS one 9 27437949
2024 The Scribble-SGEF-Dlg1 complex regulates E-cadherin and ZO-1 stability, turnover and transcription in epithelial cells. Journal of cell science 5 39350674
2024 Dexamethasone induces trabecular meshwork cell myofibroblast transdifferentiation through ARHGEF26. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 3 39092889
2026 ARHGEF26 Maintains SOX2 Stability by Inhibiting Ubiquitination to Enhance Glioblastoma Stemness. Laboratory investigation; a journal of technical methods and pathology 0 41936941
2025 SH3-containing guanine nucleotide exchange factor (SGEF) ameliorates pressure overload induced cardiac hypertrophy via enhancing EGFR-NRF2 mediated ferroptosis inhibition. Cellular signalling 0 40829739
2024 The Scribble/SGEF/Dlg1 complex regulates the stability of apical junctions in epithelial cells. bioRxiv : the preprint server for biology 0 38585765

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