ARHGEF28 (RGNEF, p190RhoGEF) is a large Lbc-family Rho guanine nucleotide exchange factor with an N-terminal IPT/TIG region, a DH/PH catalytic module and a long C-terminal region with coiled coils. Its DH/PH module activates RhoA but not Rac1 or Cdc42; the full-length protein is autoinhibited in vitro, and its PH domain binds active RhoA and Rac1, which promotes its access to RhoA-GDP. Endogenous protein is cytosolic, along microtubules, and at RhoA-rich plasma membrane regions. Downstream of fibronectin-integrin engagement it activates RhoA and, through a GEF-independent scaffolding role, recruits and activates FAK at early adhesions, supporting focal adhesion formation and cell migration. Its C-terminal region binds the neurofilament light chain mRNA, and RGNEF has been implicated in amyotrophic lateral sclerosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | EXP PMID:11058585 Characterization of p190RhoGEF, a RhoA-specific guanine nucl... | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (EXP). The p190RhoGEF DH/PH module catalyses nucleotide release from RhoA but not Rac1 or Cdc42 in vitro (RhoB and RhoC were not in that panel); the full-length protein is autoinhibited in vitro but activates RhoA in cells. Core function. Reason: [PMID:11058585 "Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays."] [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Supporting Evidence: PMID:11058585 Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays. PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (IBA). The p190RhoGEF DH/PH module catalyses nucleotide release from RhoA but not Rac1 or Cdc42 in vitro (RhoB and RhoC were not in that panel); the full-length protein is autoinhibited in vitro but activates RhoA in cells. Core function. Reason: [PMID:11058585 "Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays."] [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002677784 SUPPORTS TRANSFER Lbc-family RhoGEF node; GEF activity IBD (interpro/panther/PTHR13944/PTHR13944-paint.tsv). FB:FBgn0032796 SUPPORTS TRANSFER Drosophila cyst (RhoGEF). MGI:MGI:103264 SUPPORTS TRANSFER Mouse Arhgef2 (GEF-H1). UniProtKB:Q12802 SUPPORTS TRANSFER Human AKAP13 (Lbc). UniProtKB:Q6ZSZ5 SUPPORTS TRANSFER Human ARHGEF18. UniProtKB:Q8N1W1 SUPPORTS TRANSFER Human ARHGEF28 itself; its own experimental annotation is among the node's sources. UniProtKB:Q92974 SUPPORTS TRANSFER Human ARHGEF2 (GEF-H1). Supporting Evidence: PMID:11058585 Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays. PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (IEA). The p190RhoGEF DH/PH module catalyses nucleotide release from RhoA but not Rac1 or Cdc42 in vitro (RhoB and RhoC were not in that panel); the full-length protein is autoinhibited in vitro but activates RhoA in cells. Core function. Reason: [PMID:11058585 "Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays."] [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Supporting Evidence: PMID:11058585 Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays. PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0005085 guanyl-nucleotide exchange factor activity | TAS Reactome:R-HSA-8980691 | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (TAS, Reactome:R-HSA-8980691). The p190RhoGEF DH/PH module catalyses nucleotide release from RhoA but not Rac1 or Cdc42 in vitro (RhoB and RhoC were not in that panel); the full-length protein is autoinhibited in vitro but activates RhoA in cells. Core function. Reason: [PMID:11058585 "Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays."] [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Supporting Evidence: PMID:11058585 Here we show that the isolated tandem Dbl homology/pleckstrin homology domain of p190RhoGEF activates RhoA in vitro, but not Rac1 or Cdc42, as determined by GDP release and protein binding assays. PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0005085 guanyl-nucleotide exchange factor activity | TAS Reactome:R-HSA-9013023 | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (TAS, Reactome RHOB GTPase cycle). Reactome lists ARHGEF28 among GEFs that bind and load RHOB, from cell-based GEF screens; the term is substrate-agnostic. Accepted. Reason: [file:reactome/R-HSA-9013023.md "ARHGEF28 (Jaiswal et al. 2011; Jaiswal et al. 2013)"] Supporting Evidence: file:reactome/R-HSA-9013023.md ARHGEF28 (Jaiswal et al. 2011; Jaiswal et al. 2013) |
| GO:0005085 guanyl-nucleotide exchange factor activity | TAS Reactome:R-HSA-9013109 | ACCEPT | Summary: Guanyl-nucleotide exchange factor activity (TAS, Reactome RHOC GTPase cycle). Reactome lists ARHGEF28 among GEFs that bind and load RHOC, from cell-based GEF screens; the term is substrate-agnostic. Accepted. Reason: [file:reactome/R-HSA-9013109.md "ARHGEF28 (Jaiswal et al. 2011; Jaiswal et al. 2013)"] Supporting Evidence: file:reactome/R-HSA-9013109.md ARHGEF28 (Jaiswal et al. 2011; Jaiswal et al. 2013) |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm (IEA). A correct general parent of the accepted cytosol location; kept as non-core. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3928592 | ACCEPT | Summary: Cytosol (TAS). Endogenous p190RhoGEF localizes to the cytosol, along microtubules, and at RhoA-containing plasma membrane regions; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3928598 | ACCEPT | Summary: Cytosol (TAS). Endogenous p190RhoGEF localizes to the cytosol, along microtubules, and at RhoA-containing plasma membrane regions; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8980691 | ACCEPT | Summary: Cytosol (TAS). Endogenous p190RhoGEF localizes to the cytosol, along microtubules, and at RhoA-containing plasma membrane regions; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013023 | ACCEPT | Summary: Cytosol (TAS). Endogenous p190RhoGEF localizes to the cytosol, along microtubules, and at RhoA-containing plasma membrane regions; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013109 | ACCEPT | Summary: Cytosol (TAS). Endogenous p190RhoGEF localizes to the cytosol, along microtubules, and at RhoA-containing plasma membrane regions; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (IEA). Endogenous p190RhoGEF localizes to RhoA-containing regions at the plasma membrane, and it scaffolds FAK at early adhesions in a PH-domain-dependent manner; accepted. Reason: [PMID:11058585 "Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules."] [PMID:24006257 "These results support a scaffolding role for Rgnef in FAK localization and activation at early adhesions in a PH-domain-dependent but GEF-activity-independent manner."] Supporting Evidence: PMID:11058585 Immunofluorescence studies show that endogenous p190RhoGEF localizes to distinct RhoA-containing regions at the plasma membrane, to the cytosol and along microtubules. PMID:24006257 These results support a scaffolding role for Rgnef in FAK localization and activation at early adhesions in a PH-domain-dependent but GEF-activity-independent manner. |
| GO:0007264 small GTPase-mediated signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Small GTPase-mediated signal transduction (IBA). Correct but general; the specific role is regulation of RhoA signalling, captured on the accepted GO:0035023 row. Kept as non-core. Reason: [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002677784 SUPPORTS TRANSFER Lbc-family RhoGEF node; IBD seeded by ARHGEF18 (interpro/panther/PTHR13944/PTHR13944-paint.tsv). UniProtKB:Q6ZSZ5 SUPPORTS TRANSFER Human ARHGEF18. Supporting Evidence: PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0035023 regulation of Rho protein signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of Rho protein signal transduction (IBA). Rgnef-null fibroblasts fail to activate RhoA after fibronectin-integrin stimulation and are defective in focal adhesion formation and migration; core process. Reason: [PMID:22649559 "loss of Rgnef significantly inhibited haptotaxis migration, wound closure motility, focal adhesion number, and RhoA GTPase activation after fibronectin-integrin stimulation."] [PMID:22649559 "support an essential role for Rgnef in RhoA regulation downstream of integrins in control of cell migration."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002677784 SUPPORTS TRANSFER Lbc-family RhoGEF node; regulation of Rho signal transduction IBD (interpro/panther/PTHR13944/PTHR13944-paint.tsv). MGI:MGI:103264 SUPPORTS TRANSFER Mouse Arhgef2 (GEF-H1). UniProtKB:Q12802 SUPPORTS TRANSFER Human AKAP13 (Lbc). Supporting Evidence: PMID:22649559 loss of Rgnef significantly inhibited haptotaxis migration, wound closure motility, focal adhesion number, and RhoA GTPase activation after fibronectin-integrin stimulation. PMID:22649559 support an essential role for Rgnef in RhoA regulation downstream of integrins in control of cell migration. |
| GO:0048013 ephrin receptor signaling pathway | TAS Reactome:R-HSA-2682334 | KEEP AS NON CORE | Summary: Ephrin receptor signaling pathway (TAS, Reactome EPH-ephrin signaling). Reactome places p190RhoGEF in the EphB branch through FAK-mediated dendritic spine morphogenesis, in which p190RhoGEF binds phosphorylated FAK and activates RhoA. The link to ephrin receptors is indirect (via FAK) and comes from neuronal studies; kept as non-core. Reason: [file:reactome/R-HSA-3928598.md "p190RhoGEF binds directly to phosphorylated PTK2 through a motif in the RhoGEF C-terminal domain, a feature not shared with other GEFs"] [file:reactome/R-HSA-3928598.md "FAK-mediated spine morphogenesis was shown to occur, in part through Rho guanine nucleotide exchange factor 28 (ARHGEF28, p190RhoGEF), suggesting that FAK-mediated spine maturation might proceed through a FAK-RhoGEF-RHOA mechanism."] Supporting Evidence: file:reactome/R-HSA-3928598.md p190RhoGEF binds directly to phosphorylated PTK2 through a motif in the RhoGEF C-terminal domain, a feature not shared with other GEFs file:reactome/R-HSA-3928598.md FAK-mediated spine morphogenesis was shown to occur, in part through Rho guanine nucleotide exchange factor 28 (ARHGEF28, p190RhoGEF), suggesting that FAK-mediated spine maturation might proceed through a FAK-RhoGEF-RHOA mechanism. |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | KEEP AS NON CORE | Summary: Regulation of small GTPase mediated signal transduction (TAS, Reactome). A correct but general parent of the accepted regulation of Rho protein signal transduction; kept as non-core. Reason: [PMID:11058585 "When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription."] Supporting Evidence: PMID:11058585 When overexpressed in intact cells, however, p190RhoGEF does activate RhoA with subsequent F-actin reorganization and serum response factor-mediated transcription. |
| GO:0048041 focal adhesion assembly | IMP PMID:24006257 A non-canonical role for Rgnef in promoting integrin-stimula... | NEW | Summary: Focal adhesion assembly (NEW, IMP). Rgnef-null fibroblasts are defective in adhesion formation on fibronectin; rescue needs Rgnef-FAK binding and an intact PH domain but not GEF activity. Rgnef therefore does work in adhesion assembly as a scaffold, the role in which talin carries this term. Reason: [PMID:24006257 "Rgnef-null mouse embryo fibroblasts (MEFs) exhibit defects in adhesion formation, levels of FAK phosphotyrosine (pY)-397 and FAK localization to peripheral adhesions upon re-plating on FN. Rgnef re-expression rescues these defects, but requires Rgnef-FAK binding."] [PMID:24006257 "These results support a scaffolding role for Rgnef in FAK localization and activation at early adhesions in a PH-domain-dependent but GEF-activity-independent manner."] Supporting Evidence: PMID:24006257 Rgnef-null mouse embryo fibroblasts (MEFs) exhibit defects in adhesion formation, levels of FAK phosphotyrosine (pY)-397 and FAK localization to peripheral adhesions upon re-plating on FN. Rgnef re-expression rescues these defects, but requires Rgnef-FAK binding. PMID:24006257 These results support a scaffolding role for Rgnef in FAK localization and activation at early adhesions in a PH-domain-dependent but GEF-activity-independent manner. |
| GO:0019901 protein kinase binding | IPI PMID:24006257 A non-canonical role for Rgnef in promoting integrin-stimula... | NEW | Summary: Protein kinase binding (NEW). p190RhoGEF binds phosphorylated FAK (PTK2) directly through a C-terminal motif, and Rgnef's adhesion function requires this binding. Reason: [file:reactome/R-HSA-3928598.md "p190RhoGEF binds directly to phosphorylated PTK2 through a motif in the RhoGEF C-terminal domain, a feature not shared with other GEFs"] [PMID:24006257 "Rgnef-null mouse embryo fibroblasts (MEFs) exhibit defects in adhesion formation, levels of FAK phosphotyrosine (pY)-397 and FAK localization to peripheral adhesions upon re-plating on FN. Rgnef re-expression rescues these defects, but requires Rgnef-FAK binding."] Supporting Evidence: file:reactome/R-HSA-3928598.md p190RhoGEF binds directly to phosphorylated PTK2 through a motif in the RhoGEF C-terminal domain, a feature not shared with other GEFs PMID:24006257 Rgnef-null mouse embryo fibroblasts (MEFs) exhibit defects in adhesion formation, levels of FAK phosphotyrosine (pY)-397 and FAK localization to peripheral adhesions upon re-plating on FN. Rgnef re-expression rescues these defects, but requires Rgnef-FAK binding. |
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Experiment: Rescue Rgnef-null cells with GEF-dead, PH-domain and FAK-binding mutants side by side to separate RhoA activation from FAK scaffolding in adhesion and migration.
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