Affinage

ARHGEF18

Rho guanine nucleotide exchange factor 18 · UniProt Q6ZSZ5

Length
1361 aa
Mass
151.6 kDa
Annotated
2026-04-28
21 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGEF18 (p114RhoGEF) is a DH/PH-domain guanine nucleotide exchange factor that catalyzes RhoA activation at spatially defined cellular compartments—epithelial and endothelial tight junctions, the circumferential actomyosin belt, and mitochondrial fission sites—to drive junction assembly, apicobasal polarity, actomyosin contractility, cell migration, and organelle fission (PMID:21258369, PMID:22006950, PMID:40920138). It is activated by diverse upstream inputs including Gβγ subunits, Gα12, the FERM-domain protein Lulu2, CRB3A/Ehm2, Dishevelled/Daam1, SEPTIN9, and LKB1, with aPKC phosphorylation and shear-stress-induced phosphorylation modulating its localization and activity (PMID:14512443, PMID:31051012, PMID:22006950, PMID:39977269). Downstream, ARHGEF18-activated RhoA signals through ROCK and myosin II to control myosin light chain double-phosphorylation, cortical contractility, tubulogenesis, syncytiotrophoblast differentiation, and endothelial barrier function (PMID:23185572, PMID:26483385, PMID:33842485, PMID:39977269). Biallelic loss-of-function variants in ARHGEF18 cause retinal degeneration in humans and animal models, reflecting its essential role in maintaining neuroepithelial polarity and the outer limiting membrane (PMID:28132693, PMID:23698346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 High

    Establishing ARHGEF18 as a Gβγ-responsive RhoGEF resolved how heterotrimeric G protein signaling activates RhoA and Rac1 to induce stress fibers and ROS production.

    Evidence Co-IP, pull-down, dominant-negative mutants, and SRE reporter assays in mammalian cells

    PMID:14512443

    Open questions at the time
    • Direct GEF kinetics with purified Gβγ and RhoA not reported
    • Relative contribution to Rac1 vs. RhoA activation in physiological settings unclear
  2. 2010 Medium

    Linking ARHGEF18 to Wnt/PCP signaling via Dishevelled and Daam1 revealed how non-canonical Wnt signals funnel through a specific GEF to activate RhoA and drive neurite retraction.

    Evidence shRNA screen, Co-IP with Dvl and Daam1, dominant-negative domain constructs in neuroblastoma cells

    PMID:20810787

    Open questions at the time
    • Whether this Dvl–ARHGEF18 axis operates in non-neuronal PCP contexts not tested
    • Direct binding interface between Dvl and ARHGEF18 not mapped
  3. 2011 High

    Demonstrating that ARHGEF18 localizes to epithelial junctions and drives spatially restricted RhoA activation in complex with myosin II, ROCK II, and cingulin established it as the principal junctional RhoGEF controlling tight junction assembly and epithelial morphogenesis.

    Evidence RNAi, reciprocal Co-IP, RhoA activation assays, live imaging in epithelial cells; parallel study showed Lulu2-mediated activation and aPKC-dependent negative regulation at apical junctions

    PMID:21258369 PMID:22006950

    Open questions at the time
    • Crystal structure of ARHGEF18–cingulin or ARHGEF18–Lulu2 complex unavailable
    • Whether ARHGEF18 directly binds ROCK II or association is indirect through RhoA not resolved
  4. 2013 High

    Genetic loss-of-function in medaka and interaction studies with LKB1 extended the junctional RhoGEF model in vivo, showing ARHGEF18 is essential for retinal neuroepithelial polarity, tight junction integrity, and cell cycle regulation, with LKB1 acting as a kinase-independent scaffold.

    Evidence Medaka mutant rescued by human ARHGEF18, immunostaining, RhoA assays; Co-IP of LKB1 with kinase-dead mutant in bronchial epithelial cells

    PMID:23648482 PMID:23698346

    Open questions at the time
    • Mechanism by which ARHGEF18 loss increases proliferation in retinal neuroepithelium not defined
    • Structural basis of LKB1–ARHGEF18 interaction unknown
  5. 2012 Medium

    Showing that ARHGEF18 selectively promotes myosin light chain double-phosphorylation at cell contacts and in single migrating cells clarified its specific contribution to cortical contractility, collective migration, and amoeboid invasion.

    Evidence RNAi, mono- vs. di-phospho-MLC antibodies, Matrigel invasion, RhoA/Rac pull-down

    PMID:23185572

    Open questions at the time
    • Which kinase(s) downstream of ROCK mediate double-phosphorylation not identified
    • Relative contribution of ARHGEF18 vs. other RhoGEFs in invasive migration not compared
  6. 2015 Medium

    Placing ARHGEF18 upstream of ROCK and myosin IIA during tubulogenesis and demonstrating CRB3A-mediated recruitment with Ehm2 revealed how polarity determinants spatially engage ARHGEF18 to organize the actomyosin belt.

    Evidence RNAi plus ROCK/myosin IIA inhibitors in MDCK tubulogenesis; Co-IP and domain mutants of CRB3A in HeLa cells

    PMID:26217016 PMID:26483385

    Open questions at the time
    • Whether Ehm2 directly activates ARHGEF18 catalytic activity or only recruits it not distinguished
    • Role in in vivo tubulogenesis not confirmed
  7. 2016 Medium

    Identifying a non-canonical Gα12-binding region in the ARHGEF18 C-terminus, distinct from classic RGS-domain interactions, expanded the repertoire of heterotrimeric G protein inputs that activate this GEF.

    Evidence Co-IP with chimeric Gα12/13 constructs and charge-reversal mutagenesis

    PMID:31051012

    Open questions at the time
    • No crystal structure of Gα12–ARHGEF18 interface
    • Whether Gα12 and Gβγ act synergistically or independently on ARHGEF18 not tested
  8. 2017 Low

    Discovery of biallelic ARHGEF18 variants (p.Thr270Ala in the DH domain) in patients with retinal degeneration linked the gene to human Mendelian disease and pinpointed a catalytically essential residue.

    Evidence Human genetic analysis of patients with adult-onset retinal degeneration; domain-level functional inference

    PMID:28132693

    Open questions at the time
    • No direct biochemical reconstitution of T270A variant GEF activity reported in this study
    • Genotype–phenotype spectrum across additional families not established
  9. 2021 Medium

    Demonstrating that ARHGEF18 knockout disrupts syncytiotrophoblast differentiation and placenta development via PKA-dependent actomyosin remodeling and CREB-driven transcription revealed a non-junctional developmental function.

    Evidence Mouse knockout, in vitro trophoblast differentiation, PKA signaling and CREB reporter assays

    PMID:33842485

    Open questions at the time
    • How ARHGEF18 controls AKAP12 expression mechanistically not resolved
    • Whether RhoA is the sole mediator downstream of ARHGEF18 in trophoblast fusion unknown
  10. 2025 Medium

    Identification of SEPTIN9 as an activator of ARHGEF18 at mitochondrial fission sites, upstream of calcium influx and DRP1 recruitment, established a new organellar function for this GEF beyond junctions.

    Evidence Live-cell imaging, Co-IP, siRNA, mitochondrial calcium assays in mammalian cells

    PMID:40920138

    Open questions at the time
    • Whether ARHGEF18 activates RhoA or another GTPase at mitochondria not definitively shown
    • Mechanism linking ARHGEF18-dependent signaling to mitochondrial calcium influx not identified
  11. 2025 Medium

    Demonstrating shear-stress-induced phosphorylation of ARHGEF18 and its requirement for endothelial tight junction formation, flow-induced alignment, and vascular barrier integrity extended its junctional role to the endothelium in vivo.

    Evidence Phosphorylation assays, Co-IP with TJ proteins, endothelial KO mice, vascular permeability assays

    PMID:39977269

    Open questions at the time
    • Identity of the kinase(s) that phosphorylate ARHGEF18 under shear stress not determined
    • Phosphosite(s) responsible for TJ interaction not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural understanding of ARHGEF18 in complex with its diverse activators and effectors is lacking, and the relative contributions of RhoA vs. Rac1 activation across its varied cellular contexts remain unresolved.
  • No crystal or cryo-EM structure of ARHGEF18 or any of its complexes
  • Isoform-specific functions (e.g., eosinophil LOCGEF isoforms) not functionally characterized
  • Whether ARHGEF18 has catalytic-independent scaffold functions remains untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8
Localization
GO:0005886 plasma membrane 6 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1500931 Cell-Cell communication 5 R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
CGNCRB3EPB41L4BMYH9RHOAROCK2SEPT9STK11
Complex memberships
CRB3A–Ehm2–p114RhoGEF polarity complexLulu2–p114RhoGEF apical complexp114RhoGEF–myosin II–ROCK II–cingulin junctional complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 p114RhoGEF (ARHGEF18) is a junction-associated RhoA GEF that drives spatially restricted RhoA activation at epithelial junctions, regulates tight-junction assembly and epithelial morphogenesis, and associates with a complex containing myosin II, ROCK II, and the junctional adaptor cingulin. RNAi knockdown, Co-immunoprecipitation, RhoA activation assays, live imaging, myosin phosphorylation readouts Nature cell biology High 21258369
2003 Gβγ subunits of heterotrimeric G proteins interact with the full-length and DH/PH domain of p114RhoGEF and stimulate its GEF activity toward RhoA and Rac1 (but not Cdc42), leading to actin stress fiber formation and ROS production via NADPH oxidase. Co-immunoprecipitation, in vivo pull-down assays, dominant-negative mutants, SRE reporter assays, Gβγ scavenger (transducin) Circulation research High 14512443
2011 Lulu2 (a FERM-domain protein) directly interacts with and activates p114RhoGEF at apical cell-cell junctions to regulate the circumferential actomyosin belt; this interaction is negatively regulated by aPKC-mediated phosphorylation of the FERM-adjacent domain of Lulu2. Additionally, Patj recruits p114RhoGEF to apical cell-cell boundaries via PDZ domain-mediated interaction. Co-immunoprecipitation, RNAi knockdown, GEF activity assays, phosphorylation experiments, domain mapping The Journal of cell biology High 22006950
2013 ArhGEF18-mediated activation of RhoA is required to maintain apicobasal polarity in the vertebrate retinal neuroepithelium; RhoA signals through Rock2 to regulate tight junction localization and cortical actin. Loss of ArhGEF18 increases proliferation and reduces cell cycle exit. Human ARHGEF18 rescues the medaka mutant phenotype. Genetic mutation in medaka fish, rescue with human ARHGEF18, immunostaining, RhoA activity assays Development (Cambridge, England) High 23698346
2013 LKB1 interacts with p114RhoGEF in a kinase-activity-independent manner to control RhoA activity at apical junctions and promote apical junction assembly in human bronchial epithelial cells. Co-immunoprecipitation, kinase-dead LKB1 mutant, RhoA activation assays, RNAi knockdown Molecular and cellular biology Medium 23648482
2010 p114-RhoGEF is required for Wnt-3a- and Dishevelled-induced RhoA activation and neurite retraction in neuroblastoma cells; p114-RhoGEF physically interacts with Dvl and Daam1, and its Dvl-binding domain acts as a dominant-negative inhibitor of Dvl-induced neurite retraction. shRNA screening, RhoA activation assays, Co-immunoprecipitation, dominant-negative domain constructs Molecular biology of the cell Medium 20810787
2012 p114RhoGEF drives cortical myosin activation specifically by stimulating myosin light chain double phosphorylation (not single phosphorylation) at cell-cell contacts in migrating epithelial sheets and at the cortex of single migrating cells, promoting collective cell migration and amoeboid-like tumor cell invasion; depletion reduces RhoA but increases Rac activity. RNAi knockdown, myosin phosphorylation assays (mono- vs. double-phospho MLC), Matrigel invasion assay, RhoA/Rac pull-down assays PloS one Medium 23185572
2015 p114RhoGEF knockdown impairs late-stage tubulogenesis (lumen consolidation) in HGF-stimulated MDCK cells by blocking cell movement; ROCK and myosin IIA act downstream of p114RhoGEF-RhoA in this pathway. RNAi knockdown, ROCK/myosin IIA inhibitors, live-cell imaging of tubulogenesis Journal of cell science Medium 26483385
2015 CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery via its cytoplasmic tail motifs, increasing RhoA activation; ROCK1/2 act downstream to remodel the cytoskeleton and drive circumferential actomyosin belt formation and cell shape change in HeLa cells. Co-immunoprecipitation, domain mutants of CRB3A cytoplasmic tail, RhoA activation assays, ROCK inhibitors, immunofluorescence Molecular and cellular biology Medium 26217016
2016 p114RhoGEF contains a C-terminal region that specifically binds Gα12 (but not Gα13) independently of the canonical RGS-homology domain mechanism; charge-reversal mutagenesis of conserved residues disrupts Gα12 binding, and dominant-negative Gα12 suppresses serum-mediated signaling through p114RhoGEF in cells. Co-immunoprecipitation, chimeric Gα12/13 constructs, charge-reversal mutagenesis, dominant-negative Gα constructs Journal of molecular signaling Medium 31051012
2017 The p.Thr270Ala missense variant in the DH homology domain of ARHGEF18 (found in patients with adult-onset retinal degeneration) affects a conserved residue required for interaction with and activation of RhoA, supporting the DH domain as the catalytic interface for RhoA activation. Human genetics (biallelic mutations), functional inference from domain analysis of missense variant American journal of human genetics Low 28132693
2021 p114RhoGEF/ARHGEF18 is required for mouse syncytiotrophoblast differentiation and placenta development: it controls expression of AKAP12, is required for PKA-induced actomyosin remodeling, and promotes CREB-driven gene expression necessary for trophoblast cell-cell fusion. In vitro trophoblast differentiation assays, in vivo mouse knockouts, PKA signaling assays, CREB reporter assays, AKAP12 expression analysis Frontiers in cell and developmental biology Medium 33842485
2018 Eosinophils express novel N-terminally extended isoforms of ARHGEF18 (LOCGEF-X3/X4/X5) from an alternative transcriptional start site; upon activation (IL5, CCL11, or IL33), LOCGEF and RHOA relocalize from the cell periphery to the two poles of polarized eosinophils, implicating LOCGEF in polarity control in leukocytes. RT-PCR, molecular cloning, immunoblot, immunostaining, recombinant protein expression Journal of leukocyte biology Low 29601110
2025 SEPTIN9 is present at mitochondrial fission sites from early stages and activates ARHGEF18 locally through an isoform-specific N-terminal interaction; SEPTIN9-dependent ARHGEF18 activation is required for mitochondrial calcium influx at early fission steps, upstream of DRP1 recruitment. Live-cell imaging, Co-immunoprecipitation, siRNA knockdown, mitochondrial calcium assays, DRP1 localization The Journal of cell biology Medium 40920138
2025 ARHGEF18 is phosphorylated in response to shear stress in endothelial cells; when phosphorylated, it interacts with tight junctions and promotes EC elongation, alignment, migration, and maintenance of the endothelial barrier. In vivo, ARHGEF18 controls tight junction formation, EC flow response, and vascular permeability. Phosphorylation assays, Co-immunoprecipitation with tight junction proteins, RNAi/KO in mice, vascular permeability assays, live imaging Cell reports Medium 39977269
2025 Conditional knockout of Arhgef18 in Müller glial cells disrupts the retinal outer limiting membrane (OLM) adherens junctions and leads to progressive retinal degeneration; ARHGEF18 depletion activates NF-κB, β-catenin, and TBK1 signaling and reduces mitochondrial activity; TBK1 inhibition or nicotinamide rescues these defects. Conditional KO mouse (Müller-specific), cell culture knockdown, OLM protein immunostaining, NF-κB/β-catenin/TBK1 activity assays, mitochondrial activity assays, pharmacological rescue bioRxivpreprint Medium bio_10.1101_2025.10.07.680916

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis. Nature cell biology 188 21258369
2003 G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1: regulation of cell shape and reactive oxygen species production. Circulation research 100 14512443
2011 Lulu2 regulates the circumferential actomyosin tensile system in epithelial cells through p114RhoGEF. The Journal of cell biology 77 22006950
2013 LKB1 controls human bronchial epithelial morphogenesis through p114RhoGEF-dependent RhoA activation. Molecular and cellular biology 39 23648482
2010 Involvement of p114-RhoGEF and Lfc in Wnt-3a- and dishevelled-induced RhoA activation and neurite retraction in N1E-115 mouse neuroblastoma cells. Molecular biology of the cell 38 20810787
2013 ArhGEF18 regulates RhoA-Rock2 signaling to maintain neuro-epithelial apico-basal polarity and proliferation. Development (Cambridge, England) 33 23698346
2012 Stimulation of cortical myosin phosphorylation by p114RhoGEF drives cell migration and tumor cell invasion. PloS one 30 23185572
2017 Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. American journal of human genetics 25 28132693
2015 p114RhoGEF governs cell motility and lumen formation during tubulogenesis through a ROCK-myosin-II pathway. Journal of cell science 22 26483385
2015 CRB3A Controls the Morphology and Cohesion of Cancer Cells through Ehm2/p114RhoGEF-Dependent Signaling. Molecular and cellular biology 21 26217016
2012 The circumferential actomyosin belt in epithelial cells is regulated by the Lulu2-p114RhoGEF system. Small GTPases 16 22790195
2021 ARHGEF18/p114RhoGEF Coordinates PKA/CREB Signaling and Actomyosin Remodeling to Promote Trophoblast Cell-Cell Fusion During Placenta Morphogenesis. Frontiers in cell and developmental biology 14 33842485
2013 ArhGEF18 regulated Rho signaling in vertebrate retina development. Small GTPases 11 24231347
2016 A Gα12-specific Binding Domain in AKAP-Lbc and p114RhoGEF. Journal of molecular signaling 9 31051012
2018 Association between a Single Nucleotide Polymorphism in the 3'-UTR of ARHGEF18 and the Risk of Nonidiopathic Pulmonary Arterial Hypertension in Chinese Population. Disease markers 8 30405854
2018 Expression of novel "LOCGEF" isoforms of ARHGEF18 in eosinophils. Journal of leukocyte biology 3 29601110
2023 ARHGEF18 can promote BVDV NS5B activation of the host NF-κB signaling pathway by combining with the NS5B-palm domain. Veterinary microbiology 2 38367539
2025 ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage. Cell reports 1 39977269
2025 SEPTIN9 locally activates the RhoGEF ARHGEF18 to promote early stages of mitochondrial fission. The Journal of cell biology 1 40920138
2023 Establishment and identification of cardiomyocyte arhGEF18 gene conditional knockout mice. Pediatric discovery 1 40625715
2025 Establishment and functional studies of a model of cardiomyopathy with cardiomyocyte-specific conditional knockout of Arhgef18. Disease models & mechanisms 0 40159883