Affinage

ARHGEF12

Rho guanine nucleotide exchange factor 12 · UniProt Q9NZN5

Length
1544 aa
Mass
173.2 kDa
Annotated
2026-04-28
84 papers in source corpus 39 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGEF12 (LARG) is a RhoA-specific guanine nucleotide exchange factor (GEF) that serves as the principal signaling conduit from Gα12/13-coupled GPCRs and mechanical stimuli to RhoA-dependent cytoskeletal remodeling, smooth muscle contraction, cell migration, and cytokinesis. Its DH domain catalyzes nucleotide exchange on RhoA/B/C with ~10⁷-fold acceleration—the highest reported for a Dbl-family GEF—and in specific endothelial contexts also activates Rap1A (PMID:21454492, PMID:35294066). LARG is regulated by multiple upstream inputs: direct binding of activated Gα12/13 and Gαq, plexin-B receptor engagement via its PDZ domain, integrin/Fyn kinase-mediated mechanotransduction, RSK2 phosphorylation at Ser1288 (promoting membrane translocation and RhoA complex assembly), Cdk1 phosphorylation during mitosis (attenuating activity), CYLD-mediated deubiquitination (enhancing activity), TGF-β-driven proteasomal degradation, and a C-terminal autoinhibitory region that oligomerizes with PDZ-RhoGEF (PMID:11094164, PMID:12196628, PMID:21572419, PMID:29279389, PMID:26483157, PMID:23405219, PMID:25143398, PMID:14712228). In vivo, smooth-muscle-specific LARG loss abolishes myogenic vasoconstriction and salt-induced hypertension, airway LARG knockout attenuates allergen-induced hyperresponsiveness, and LARG is required for erythroid differentiation through a RhoA–p38 kinase axis (PMID:31549965, PMID:18084302, PMID:30385725, PMID:31467124).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Established that LARG is an effector of Gα12-family heterotrimeric G proteins that activates RhoA, filling the mechanistic gap between G12/13-coupled GPCRs and Rho-dependent signaling.

    Evidence In vivo RhoA activation assays and co-expression with Gα12 family proteins in mammalian cells

    PMID:11094164

    Open questions at the time
    • Structural basis of Gα12/13–LARG interaction undefined
    • Relative contribution versus other RGS-RhoGEFs unclear
  2. 2002 High

    Identified two distinct upstream activation mechanisms—plexin-B receptors via PDZ domain binding and FAK-mediated tyrosine phosphorylation—revealing LARG as an integrator of receptor tyrosine kinase and GPCR signals toward RhoA.

    Evidence Affinity pulldown, PDZ domain mutagenesis, dominant-negative experiments for plexin-B1/B2; FAK co-expression with phosphorylation detection and RhoA-GTP pulldown

    PMID:11799111 PMID:12183458 PMID:12196628

    Open questions at the time
    • Tyrosine phosphorylation sites on LARG not mapped
    • Whether plexin and FAK inputs are synergistic or parallel was not tested
  3. 2004 High

    Revealed a C-terminal autoinhibitory domain that mediates homo- and hetero-oligomerization with PDZ-RhoGEF and restrains in vivo GEF activity, explaining how LARG is kept inactive in the absence of upstream signals.

    Evidence Co-immunoprecipitation, SRE reporter, in vitro GEF assay, and transformation assays with C-terminal deletion mutants

    PMID:14712228

    Open questions at the time
    • Identity of the oligomerization interface not defined
    • Mechanism by which upstream signals relieve C-terminal autoinhibition unknown
  4. 2007 High

    Demonstrated that LARG operates at specific subcellular sites (MTOC, microtubules) and in multiple signaling contexts—integrin engagement, formin (mDia1) positive feedback, and vascular smooth muscle—establishing it as a spatially regulated, context-dependent RhoA activator with in vivo physiological importance for salt-induced hypertension.

    Evidence Smooth-muscle-specific Cre/loxP KO mice with blood pressure measurement; immunofluorescence with pericentrin; in vitro GEF assay with mDia1 FH2 domain; siRNA KD with activated-GEF pulldown upon fibronectin adhesion

    PMID:17575049 PMID:17959834 PMID:17971419 PMID:18084302

    Open questions at the time
    • How pericentrin–LARG interaction is regulated was not resolved
    • Whether mDia1-LARG feedback operates in vivo untested
  5. 2009 Medium

    Extended the receptor repertoire to RGMa/neogenin guidance signaling (growth cone collapse) and showed mDia1 is required upstream of LARG activation in neutrophil chemotaxis, positioning LARG as a common Rho-activating node in both axon guidance and immune cell migration.

    Evidence Co-IP with Unc5B; mDia1-KO neutrophil chemotaxis assays; RhoA-GTP pulldowns; growth cone collapse assay

    PMID:19265163 PMID:19273616

    Open questions at the time
    • Direct binding between mDia1 and LARG in neutrophils not shown
    • How FAK phosphorylation of LARG in growth cones differs from the GPCR context unknown
  6. 2011 High

    Defined the biochemical parameters of LARG catalysis (~10⁷-fold acceleration, RhoA/B/C-specific), identified a PH domain hydrophobic patch essential for in vivo but not in vitro activity, established Fyn kinase as the mechanotransduction-specific activator of LARG, and linked Gαq to LARG activation independent of PLCβ.

    Evidence In vitro GEF kinetics with fluorescent nucleotide exchange; PH domain mutagenesis with SRF reporter; magnetic bead force on integrins with Fyn inhibition; co-IP of Gαq with LARG DH-PH

    PMID:19560536 PMID:21454492 PMID:21572419 PMID:22100544

    Open questions at the time
    • PH domain hydrophobic patch binding partner in cells not identified
    • Structural basis of Gαq–LARG DH-PH interaction undefined
  7. 2013 High

    Systematic compound KO of all three RGS-RhoGEFs proved they are the primary conduits from Gα12/13 to RhoA, and separately, CYLD deubiquitinase was identified as a post-translational activator of LARG, adding ubiquitination to the regulatory repertoire.

    Evidence Single and compound KO mice/MEFs with RhoA-GTP, JNK/p38, migration readouts; co-IP and ubiquitination assay for CYLD–LARG

    PMID:23405219 PMID:23467409

    Open questions at the time
    • Ubiquitin chain type and specific lysine residues on LARG not mapped
    • Whether CYLD regulation is cell-type-specific unknown
  8. 2013 High

    Established a mitotic function for LARG: it localizes to spindle poles and the midbody and is specifically required for abscission, resolving why LARG depletion causes cytokinesis failure and apoptosis without affecting furrow ingression.

    Evidence siRNA KD with live-cell imaging, immunofluorescence at midbody, siRNA-resistant rescue, Aurora-B inhibition rescue

    PMID:23885121

    Open questions at the time
    • How LARG is recruited to the midbody is unknown
    • Whether RhoA activation at the midbody by LARG is regulated by the same upstream inputs as in interphase
  9. 2014 High

    Expanded LARG's roles to ICAM-1-mediated mechanotransduction in endothelial cells (controlling leukocyte transmigration), TGF-β-induced proteasomal degradation during EMT (increasing invasion), centrosome integrity and replication stress signaling, and angiotensin II-mediated vascular contraction.

    Evidence Magnetic bead force on ICAM-1 clusters with TEM assay; TGF-β/ALK5 treatment with proteasome inhibitor rescue and AFM; yeast 2-hybrid/co-IP with TELO2/PCNT and γH2AX/Chk1 assays; siRNA KD with isometric aortic ring contraction

    PMID:23123644 PMID:24585879 PMID:25143398 PMID:25485589

    Open questions at the time
    • E3 ubiquitin ligase targeting LARG for proteasomal degradation during EMT not identified
    • Direct role of LARG GEF activity at centrosomes in replication stress signaling not reconstituted
  10. 2015 High

    Cdk1 phosphorylation of LARG at Ser190/Ser1176 was identified as a cell-cycle-dependent inhibitory modification, explaining how LARG activity is restrained during early mitosis and then released for abscission.

    Evidence In vitro Cdk1 kinase assay; phosphonull/phosphomimetic mutants with RhoA-GTP pulldown; phosphospecific antibodies with cell-cycle synchronization

    PMID:26483157

    Open questions at the time
    • Whether phosphatase(s) reversing Cdk1 phosphorylation at mitotic exit are identified
    • In vivo consequence of Cdk1-site mutations on cytokinesis completion not tested
  11. 2017 High

    RSK2 was identified as a direct kinase phosphorylating LARG at Ser1288 to activate RhoA/B-dependent migration and invasion, and LARG was shown to mediate mechanical strain-driven RhoA activation in mesenchymal stem cell lineage commitment.

    Evidence In vitro kinase assay; phosphospecific antibody; migration/invasion assays with EGF; siRNA KD with mechanical strain and adipogenesis readouts in MSCs

    PMID:29208526 PMID:29279389

    Open questions at the time
    • Whether RSK2 phosphorylation at Ser1288 affects LARG interaction with its autoinhibitory C-terminus unknown
    • Upstream mechanosensor linking strain to LARG in MSCs not identified
  12. 2018 High

    Arhgef12-knockout mice demonstrated that LARG is required for IL-17A-induced RhoA activation in airway smooth muscle and for allergen-induced airway hyperresponsiveness, establishing a non-vascular smooth muscle role.

    Evidence Arhgef12-KO mice; tracheal ring contractility; RhoA-GTP pulldown; house dust mite allergen model

    PMID:30385725

    Open questions at the time
    • Whether other RGS-RhoGEFs partially compensate in airway smooth muscle not tested
    • Mechanism of IL-17A receptor coupling to LARG undefined
  13. 2019 High

    Smooth-muscle-specific Gα12/13–LARG loss eliminated myogenic vasoconstriction and reduced systemic vascular resistance (without affecting Ca²⁺ signaling), and separately LARG was shown to be required for erythropoiesis via a RhoA–p38 kinase axis across zebrafish, mouse, and human systems.

    Evidence Conditional KO mice with pressure myography and hemodynamics; morpholino/CRISPR KO in zebrafish; siRNA in K562/32D cells; primary murine BM; rescue with CA-RhoA/p38

    PMID:31467124 PMID:31549965

    Open questions at the time
    • Molecular link between LARG/RhoA and p38 activation in erythroid cells not defined
    • Whether vascular phenotype is entirely RhoA-dependent or partly Rap1-mediated unknown
  14. 2022 Medium

    Challenged the RhoA-exclusive paradigm by demonstrating that in dermal microvascular endothelial cells, LARG activates Rap1A (not RhoA) to protect capillary barrier integrity, revealing an unexpected substrate selectivity switch.

    Evidence Cell-free GEF assay on multiple GTPases; siRNA KD with transendothelial electrical resistance

    PMID:35294066

    Open questions at the time
    • Structural basis for Rap1A selectivity undefined
    • Whether Rap1A activation by LARG occurs in other cell types not tested
    • Not independently confirmed by another lab
  15. 2023 High

    Optogenetic Rac activation showed LARG is recruited to the plasma membrane by active Rac, mediating Rac-to-Rho crosstalk that controls protrusion–retraction dynamics during exploratory cell migration.

    Evidence Optogenetic Rac activation with FRET-based Rho biosensors; siRNA KD; live-cell migration tracking; TIRF imaging

    PMID:38102112

    Open questions at the time
    • Molecular adaptor linking active Rac to LARG membrane recruitment not identified
    • Whether this Rac-to-Rho conversion operates in 3D migration contexts unknown
  16. 2025 High

    Mechanistic detail of RSK2-LARG signaling was refined: Ser1288 phosphorylation drives LARG membrane translocation and assembly of a LARG–RhoA complex in glioblastoma cells; separately, an E620K gain-of-function mutant activates a Rap1–ITGA6–exosome axis promoting ovarian metastasis of gastric cancer.

    Evidence Membrane fractionation with phosphomimetic/null mutants; co-IP; patient tissue IHC; xenograft model with E620K mutant; exosome isolation and fibroblast CAF induction

    PMID:40860157 PMID:41338458

    Open questions at the time
    • How Ser1288 phosphorylation structurally alters LARG conformation not resolved
    • E620K mutant mechanism (why it switches to Rap1 preference) undefined
    • E620K finding from single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural model of LARG showing how its multiple regulatory inputs (Gα12/13, Gαq, PDZ ligands, Cdk1/RSK2 phosphorylation, C-terminal autoinhibition, ubiquitination) are integrated to control DH domain activity and substrate selectivity (RhoA vs. Rap1A) remains unavailable.
  • No full-length LARG structure exists
  • Molecular basis of context-dependent Rap1A versus RhoA substrate switching is unknown
  • E3 ligase(s) mediating TGF-β-driven LARG degradation not identified
  • Whether LARG plays a direct catalytic role at the centrosome/replication stress checkpoint versus a scaffolding role is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-397014 Muscle contraction 2 R-HSA-1500931 Cell-Cell communication 1
Partners
CYLDDIAPH1GNA12GNA13GNAQPCNTPLXNB1RPS6KA3

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 LARG/ARHGEF12 activates RhoA in vivo and serves as an effector linking Gα12-family heterotrimeric G proteins to Rho-dependent signaling pathways downstream of GPCRs. In vivo RhoA activation assays; co-expression with Gα12 family proteins; dominant-negative and overexpression experiments in cells FEBS letters High 11094164
2002 LARG interacts directly with the cytoplasmic domain of plexin-B1 (and plexin-B2) via its PDZ domain binding to a PDZ-binding motif in the B-family plexin C-terminus; this interaction mediates semaphorin 4D-induced RhoA activation and cytoskeletal reorganization. Affinity pulldown from mouse brain lysate; direct biochemical binding assays; PDZ domain mutagenesis; dominant-negative LARG PDZ domain overexpression blocking Sema4D-induced cell rounding Proceedings of the National Academy of Sciences of the United States of America / The Journal of biological chemistry High 12183458 12196628
2002 LARG and PDZ-RhoGEF can be tyrosine-phosphorylated by focal adhesion kinase (FAK) downstream of thrombin receptor/GPCR activation, and this phosphorylation enhances RhoA activation in vivo, identifying FAK as a component of a positive-feedback loop sustaining Rho activation. In-cell RhoA-GTP pulldown; tyrosine kinase inhibitor treatment; co-expression of FAK with LARG/PDZ-RhoGEF; phosphorylation detection by immunoprecipitation The Journal of biological chemistry High 11799111
2004 LARG forms homo- and hetero-oligomers with PDZ-RhoGEF via its unique C-terminal region; deletion of this C-terminal inhibitory region greatly increases in vivo RhoA-GEF activity and transforming potential without affecting in vitro catalytic activity, revealing a novel C-terminus-mediated autoinhibitory mechanism. Co-immunoprecipitation; SRE reporter assays; in vitro GEF assay; colony formation/transformation assays Oncogene High 14712228
2007 G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension but not for basal blood pressure; LARG links G12/G13 to the Rho/Rho kinase pathway controlling myosin light chain phosphorylation. Inducible smooth muscle-specific Cre/loxP knockout of G12, G13, and LARG in mice; blood pressure measurement; DEOXYCORTICOSTERONE-salt hypertension model Nature medicine High 18084302
2007 Dia1 (mDia1 formin) binds LARG in a RhoA-dependent (autoinhibition-release) manner, and the Dia1 FH2 domain directly stimulates the GEF activity of LARG in vitro, constituting a positive feedback loop for RhoA activation during LPA-stimulated bleb-associated cancer cell invasion. Co-immunoprecipitation; in vitro GEF assay with purified FH2 domain and LARG; Dia1 knockdown with RhoA/ROCK readouts; live-cell invasion assay Genes & development High 17575049
2007 LARG associates with pericentrin and localizes to the microtubule-organizing center (MTOC) and along microtubule tracks; Gα12/13-LARG signaling is required for MTOC polarity and microtubule dynamics during directed cell migration. Immunofluorescence colocalization; Gα12/13-deficient MEFs; MTOC polarity assay; microtubule dynamics imaging Molecular biology of the cell Medium 17959834
2007 LARG (together with Lsc/p115RhoGEF) is activated downstream of fibronectin adhesion and is required for RhoA activation, stress fiber formation, and focal adhesion formation in response to integrin engagement. Affinity pulldown for activated GEFs; siRNA knockdown of LARG and Lsc; dominant-negative Lsc overexpression; RhoA-GTP pulldown; immunofluorescence Journal of cell science High 17971419
2009 Unc5B acts as a co-receptor with neogenin for RGMa, and LARG associates with Unc5B to transduce RhoA activation; FAK mediates RGMa-induced tyrosine phosphorylation of LARG and subsequent RhoA activation underlying growth cone collapse. Co-immunoprecipitation; siRNA knockdown; RhoA-GTP pulldown; growth cone collapse assay The Journal of cell biology Medium 19273616
2009 mDia1 is required for activation of the LARG/RhoA/ROCK signaling axis during neutrophil chemotaxis; mDia1-deficient neutrophils show impaired chemoattractant-induced LARG activation, RhoA activation, ROCK activation, polarization, and directional migration. mDia1-knockout mouse neutrophils; RhoA-GTP pulldown; ROCK activity assay; chemotaxis assay; immunofluorescence Journal of immunology Medium 19265163
2009 The LARG pleckstrin homology (PH) domain contains a conserved hydrophobic patch that is critical for RhoA activation in cells; mutation of this patch abolishes stress fiber formation and RhoA activation in cells but has no effect on nucleotide exchange activity in vitro, and membrane recruitment by active Gα13 cannot rescue this defect. Mutagenesis of PH domain hydrophobic patch; SRF-luciferase transcriptional assay; confocal microscopy for stress fibers; in vitro GEF assay; membrane targeting rescue experiments Cellular signalling High 19560536
2010 S1P receptor 2 (S1PR2) activates RhoA in smooth muscle cells specifically through LARG (not other RGS-RhoGEFs), and LARG-mediated RhoA activation promotes smooth muscle cell differentiation marker gene expression while its knockdown promotes migration. Receptor-specific agonists/antagonists; siRNA knockdown of LARG, PDZ-RhoGEF, p115; RhoA-GTP pulldown; SMC differentiation marker expression; scratch wound and transwell migration assays Arteriosclerosis, thrombosis, and vascular biology High 20702813
2011 LARG is activated by tensional force applied to integrins and is recruited to adhesion complexes; LARG activation is mediated by the Src-family kinase Fyn (not ERK/FAK as for GEF-H1), and both LARG and GEF-H1 regulate force-induced RhoA activation, cellular stiffening (reinforcement), and stress fiber formation. Magnetic bead force application to integrins; biochemical GEF activation assay; siRNA knockdown; Fyn kinase inhibition/knockdown; traction force microscopy; RhoA-GTP pulldown Nature cell biology High 21572419
2011 The catalytic DH domain of LARG is a highly specific GEF for RhoA, RhoB, and RhoC (inactive toward Rac1, Cdc42, TC10) and exhibits the highest catalytic acceleration (~10^7-fold) reported for a Dbl-family GEF; a novel N-terminal regulatory region of the DH domain contributes to GDP-RhoA binding. In vitro GEF kinetics assays (fluorescence nucleotide exchange); comparative analysis of DH domains across p115, p190, PDZ-RhoGEF, LARG; fluorescently labeled RhoA binding assays The Journal of biological chemistry High 21454492
2011 LARG links the histamine H1 receptor (Gq-coupled) to RhoA activation; activated Gαq physically interacts with the DH-PH domains of LARG, and this interaction requires the LARG PDZ domain for SRF-dependent transcriptional signaling; this represents a Gq-mediated pathway for LARG activation distinct from PLCβ. Co-immunoprecipitation of Gαq with LARG fragments; SRF-luciferase reporter; dominant-negative constructs; pharmacological Gq-specific receptor (HRH1) stimulation in COS-7 and HeLa cells Cellular signalling Medium 22100544
2012 NIS (sodium/iodide symporter) binds directly to LARG and sequesters it, regulating LARG-dependent RhoA activation and thereby modulating cancer cell migration and invasion; intracellular NIS mislocalization (as seen in carcinomas) releases LARG and further increases motility. Co-immunoprecipitation of NIS and LARG; NIS knockdown/overexpression; RhoA-GTP pulldown; migration/invasion assays Cancer research Medium 22962269
2013 PDZ-RhoGEF and LARG together are essential for embryonic development; combined knockout is embryonic lethal. Triple knockout of PDZ-RhoGEF, LARG, and p115 abolishes Gα12/13-dependent signaling to RhoA, demonstrating that these RGS-RhoGEFs are the primary conduits from Gα12/13-coupled GPCRs to Rho-dependent cell proliferation, directional migration, and JNK/p38 nuclear signaling. Knockout mice (single and compound); MEF signaling assays; RhoA-GTP pulldown; JNK/p38 phosphorylation assays; cell migration and proliferation assays The Journal of biological chemistry High 23467409
2013 CYLD deubiquitinase interacts with LARG and removes ubiquitin from LARG; CYLD-mediated deubiquitination of LARG enhances its GEF activity toward RhoA, and CYLD depletion impairs RhoA-mediated cytoskeletal rearrangement, chromosome separation, and cell polarization. Co-immunoprecipitation; ubiquitination assays; RhoA-GTP pulldown; knockdown phenotypic analysis PloS one Medium 23405219
2013 LARG is required for abscission (the final stage of cytokinesis); it colocalizes with α-tubulin at spindle poles and condenses at the midbody with RhoA; LARG depletion causes apoptosis during cytokinesis with unresolved intercellular bridges and delayed fission kinetics without affecting earlier cytokinetic events (furrow regression) or internal mitotic timing. siRNA knockdown; live-cell imaging; immunofluorescence colocalization with tubulin/RhoA at midbody; rescue with siRNA-resistant LARG; Aurora-B inhibition rescue Molecular biology of the cell High 23885121
2014 LARG acts downstream of clustered ICAM-1 in endothelial cells to increase RhoA activity; this pathway is further enhanced by mechanical force on ICAM-1, and LARG depletion decreases leukocyte crawling and inhibits transendothelial migration (TEM). Magnetic bead force application to ICAM-1 clusters; siRNA knockdown of LARG; RhoA-GTP pulldown; AFM cell stiffness measurement; leukocyte TEM assay Journal of immunology High 24585879
2014 TGF-β-induced EMT promotes proteasomal degradation of LARG (and GEF-H1) through ALK5, reducing cellular stiffness and abrogating the normal stiffening response to integrin force; this LARG suppression mechanistically contributes to increased invasion capacity during EMT. TGF-β treatment; ALK5 inhibition; proteasome inhibitor rescue; AFM/cell stiffness; siRNA knockdown of LARG; invasion assays Molecular biology of the cell High 25143398
2014 Angiotensin II activates LARG via the AT1 receptor; LARG in turn activates the RhoA/MYPT1 axis in vascular smooth muscle cells, and LARG siRNA knockdown reduces Ang II-induced vascular contraction. siRNA knockdown; qPCR; Western blot for MYPT1 phosphorylation; RhoA-GTP pulldown; isometric contraction assay on rat aortic rings Acta pharmacologica Sinica Medium 23123644
2014 Jun kinase (JNK) activity mediates cytokine (IL-1β, TNF-α)-induced overexpression of LARG in colonic longitudinal smooth muscle cells, leading to hyperactivation of the ACh→Gα12→LARG→RhoA/ROCK pathway and sustained muscle hypercontraction during inflammation. JNK inhibitor (SP600125); siRNA knockdown; qPCR and Western blot; RhoA-GTP pulldown; smooth muscle contraction assay; TNBS colitis mouse model American journal of physiology. Cell physiology Medium 24740538
2015 LARG undergoes mitotic phosphorylation by Cdk1 at serine 190 and serine 1176; this phosphorylation is cell cycle-dependent (onset of mitosis, reversed at exit), phosphonull LARG is more active than phosphomimetic LARG in RhoA activation assays, and phosphorylated LARG localizes to mitotic organizing centers and the midbody. Cdk1 inhibitor treatment; in vitro kinase assay; phosphonull and phosphomimetic mutagenesis; phosphospecific antibodies; immunofluorescence; RhoA-GTP pulldown Cellular signalling High 26483157
2015 C-RGMa activates LARG/Rho/ROCK signaling to inhibit axonal growth and regulate layer-specific targeting in the optic tectum; dominant-negative LARG-PDZ expression phenocopies C-RGMa overexpression in redirecting retinal projections, genetically placing LARG downstream of C-RGMa/neogenin. In ovo electroporation; dominant-negative LARG-PDZ overexpression; retinal axon tracing in chick embryo tectum; epistasis analysis Cell death and differentiation Medium 26292756
2017 RSK2 directly phosphorylates LARG at Ser1288, which activates RhoA and RhoB (but not RhoC) signaling and promotes directed cell migration and invasion; RSK2 requires phosphorylation at Thr577 to activate LARG, and RSK2 directly interacts with LARG and with nucleotide-bound Rho isoforms. In vitro kinase assay (RSK2 phosphorylating LARG); co-immunoprecipitation; phospho-specific antibody; RhoA/B/C-GTP pulldown; RNAi knockdown; migration/invasion assays; EGF stimulation Proceedings of the National Academy of Sciences of the United States of America High 29279389
2017 LARG (knockdown) is required for mechanical strain-induced RhoA activation in mesenchymal stem cells (MSCs); LARG depletion accelerates adipogenesis and impairs mechanical suppression of adipogenesis, identifying LARG as the critical GEF mediating force-driven RhoA activation in MSC lineage determination. siRNA knockdown; mechanical strain application; RhoA-GTP pulldown; Oil-Red-O staining for adipogenesis; qPCR of differentiation markers Bone Medium 29208526
2017 LARG associates with the DC-SIGN/LSP1 signalosome complex in dendritic cells; cocaine-induced activation of LARG via DC-SIGN promotes RhoA/FAK/Pyk2/paxillin signaling and infectious synapse formation for HIV-1 DC-to-T-cell transmission. Co-immunoprecipitation; siRNA knockdown; RhoA-GTP pulldown; HIV-1 infection/transmission assay; intracellular trafficking imaging Scientific reports Medium 28094782
2018 Arhgef12 is highly expressed in airway smooth muscle and is required for IL17A-induced RhoA activation and airway contractility; Arhgef12-knockout mice show decreased airway hyperresponsiveness in a house dust mite allergy model without effects on airway inflammation. Ribosomal pulldown/qPCR profiling; Arhgef12-KO mice; tracheal ring contractility assay; RhoA-GTP pulldown; RhoGEF inhibitor treatment; allergen sensitization model JCI insight High 30385725
2019 G12/G13 and LARG (ARHGEF12) in smooth muscle cells are required for myogenic vasoconstriction; smooth muscle-specific loss-of-function leads to loss of RhoA activation (but not Ca2+ increase), increased peripheral organ perfusion, reduced systemic vascular resistance, cardiac remodeling, and aggravated hypotension during endotoxemia. Smooth muscle-specific KO mice (Cre/loxP); pressure myography; RhoA-GTP pulldown; intracellular Ca2+ measurement; in vivo hemodynamic measurements; LPS endotoxemia model eLife High 31549965
2019 ARHGEF12-RhoA-p38 kinase signaling is required for erythroid differentiation; ARHGEF12 knockdown/knockout impairs erythropoiesis at the pro-erythroblast stage in human K562 cells, mouse bone marrow, and zebrafish; active RhoA or active p38 rescues the impaired erythropoiesis. Morpholino knockdown and CRISPR/Cas9 KO in zebrafish; siRNA in K562/32D cells; primary murine bone marrow; GATA1-luciferase reporter for SNP effect; p38 kinase activity assay; rescue with constitutively active RhoA/p38 Haematologica High 31467124
2022 In TJ-forming human dermal microvascular endothelial cells, ArhGEF12 activates Rap1A (not RhoA) to limit TNF-induced capillary barrier disruption; in cell-free assays, immunoprecipitated ArhGEF12 can catalyze nucleotide exchange on both Rap1A and RhoA with high selectivity (not acting on Rap1B, Rap2A-C, RhoB, or RhoC). Active GEF pulldown assay; siRNA knockdown with trans-endothelial electrical resistance measurement; cell-free GEF assay on multiple GTPases; immunoprecipitation of active ArhGEF12 FASEB journal Medium 35294066
2023 ARHGEF12 (and Arhgef11/PDZ-RhoGEF) are recruited to the plasma membrane by active Rac at transient cell protrusions and retractions; their depletion reduces Rac-to-Rho activity crosstalk, cell protrusion-retraction dynamics, migration distance, and increases directionality, establishing these GEFs as coordinators of Rac-stimulated Rho activation during exploratory migration. Optogenetic Rac activation combined with FRET-based Rho activity biosensors; siRNA knockdown of Arhgef11/12; live-cell migration tracking; TIRF membrane localization imaging Nature communications High 38102112
2025 RSK2-mediated phosphorylation of LARG at Ser1288 promotes LARG membrane translocation and markedly enhances assembly of the LARG-RhoA complex and subsequent RhoA-GTP loading; this mechanism operates in glioblastoma cells in response to EGF. Phospho-specific antibodies; membrane fractionation; co-immunoprecipitation; RhoA-GTP pulldown; phosphomimetic/phosphonull mutants; EGF stimulation; GBM patient tissue immunostaining The Journal of biological chemistry High 41338458
2025 The ARHGEF12 E620K mutant activates ITGA6 expression through Rap1 signaling (not RhoA), promotes tumor-derived ITGA6-high exosome formation taken up by ovarian fibroblasts, and drives pre-metastatic niche formation contributing to ovarian metastasis of gastric cancer. Ectopic expression of E620K mutant; in vitro migration/invasion/colony formation; xenograft mouse model; Rap1 GTPase pulldown; exosome isolation and uptake assays; fibroblast CAF induction Theranostics Medium 40860157
2014 LARG interacts with TELO2 and PCNT; a subset of LARG co-localizes with PCNT at the centrosome; LARG-deficient cells exhibit supernumerary centrosomes, reduced replication stress-induced γH2AX and RPA foci, reduced Chk1 activation, and sensitivity to hydroxyurea/mitomycin C, establishing LARG as required for efficient replication stress signaling. Yeast 2-hybrid; co-immunoprecipitation; immunofluorescence colocalization; siRNA KD; γH2AX and RPA foci quantification; Chk1 phosphorylation; drug sensitivity assays Cell cycle Medium 25485589
2006 A Tyr1306Cys variant in LARG reduces GEF activity in transfection assays in NIH3T3 cells, and carriers of the Cys1306 allele in Pima Indians show increased in vivo insulin-mediated glucose uptake, suggesting LARG-RhoA signaling limits insulin action in skeletal muscle. Genetic association in hyperinsulinemic-euglycemic clamp study; transient transfection GEF activity assay (NIH3T3 cells) Diabetes Medium 16644711
2026 Solo (a RhoGEF) interacts with LARG, recruits it to basal cell-substrate adhesion sites, and maintains LARG activity required for actin polymerization in response to substrate stiffness; Solo and LARG together coordinate actin cytoskeletal remodeling cooperatively with PDZ-RhoGEF. BioID proximity labeling; co-immunoprecipitation; siRNA double knockdown; immunofluorescence; actin polymerization assay; substrate stiffness (hydrogel) experiments Molecular biology of the cell Medium 41739636

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nature medicine 572 18084302
2011 The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nature cell biology 303 21572419
2000 Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho. FEBS letters 199 11094164
2002 Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. The Journal of biological chemistry 188 12183458
2002 The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proceedings of the National Academy of Sciences of the United States of America 151 12196628
2007 Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes & development 141 17575049
2002 Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase. The Journal of biological chemistry 135 11799111
2004 Homo- and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential. Oncogene 93 14712228
2007 A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. Journal of cell science 92 17971419
2009 The mDial formin is required for neutrophil polarization, migration, and activation of the LARG/RhoA/ROCK signaling axis during chemotaxis. Journal of immunology (Baltimore, Md. : 1950) 81 19265163
2015 ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure. Human molecular genetics 78 25637523
2009 Unc5B associates with LARG to mediate the action of repulsive guidance molecule. The Journal of cell biology 72 19273616
2011 Mechanistic insights into specificity, activity, and regulatory elements of the regulator of G-protein signaling (RGS)-containing Rho-specific guanine nucleotide exchange factors (GEFs) p115, PDZ-RhoGEF (PRG), and leukemia-associated RhoGEF (LARG). The Journal of biological chemistry 58 21454492
2000 Effects of NO donors and synthase agonists on endothelial cell uptake of L-Arg and superoxide production. American journal of physiology. Cell physiology 58 10644521
2013 PDZ-RhoGEF and LARG are essential for embryonic development and provide a link between thrombin and LPA receptors and Rho activation. The Journal of biological chemistry 56 23467409
2014 The RhoA guanine nucleotide exchange factor, LARG, mediates ICAM-1-dependent mechanotransduction in endothelial cells to stimulate transendothelial migration. Journal of immunology (Baltimore, Md. : 1950) 50 24585879
2014 TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Molecular biology of the cell 45 25143398
2007 LARG and mDia1 link Galpha12/13 to cell polarity and microtubule dynamics. Molecular biology of the cell 45 17959834
2002 Characterization of the expression of PDZ-RhoGEF, LARG and G(alpha)12/G(alpha)13 proteins in the murine nervous system. The European journal of neuroscience 45 12492428
2010 Sphingosine 1-phosphate receptor 2 signals through leukemia-associated RhoGEF (LARG), to promote smooth muscle cell differentiation. Arteriosclerosis, thrombosis, and vascular biology 44 20702813
2012 Iodide transporter NIS regulates cancer cell motility and invasiveness by interacting with the Rho guanine nucleotide exchange factor LARG. Cancer research 41 22962269
2017 RSK2 drives cell motility by serine phosphorylation of LARG and activation of Rho GTPases. Proceedings of the National Academy of Sciences of the United States of America 40 29279389
2009 High-throughput screening for small-molecule inhibitors of LARG-stimulated RhoA nucleotide binding via a novel fluorescence polarization assay. Journal of biomolecular screening 40 19196702
2009 LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast and colorectal cancer. Oncogene 31 19734946
2023 Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles. Nature communications 27 38102112
2017 LARG GEF and ARHGAP18 orchestrate RhoA activity to control mesenchymal stem cell lineage. Bone 27 29208526
2003 Anti-thrombotic activity of PDR, a newly synthesized L-Arg derivative, on three thrombosis models in rats. Thrombosis research 24 12893027
2013 Leukemia-associated RhoGEF (LARG) is a novel RhoGEF in cytokinesis and required for the proper completion of abscission. Molecular biology of the cell 22 23885121
2009 A conserved hydrophobic surface of the LARG pleckstrin homology domain is critical for RhoA activation in cells. Cellular signalling 22 19560536
2019 MicroRNA-214-3p Regulates Hypoxia-Mediated Pulmonary Artery Smooth Muscle Cell Proliferation and Migration by Targeting ARHGEF12. Medical science monitor : international medical journal of experimental and clinical research 21 31373336
2019 ARHGEF12 regulates erythropoiesis and is involved in erythroid regeneration after chemotherapy in acute lymphoblastic leukemia patients. Haematologica 21 31467124
2014 Automated NMR fragment based screening identified a novel interface blocker to the LARG/RhoA complex. PloS one 21 24505392
2019 Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance. eLife 19 31549965
2013 Modulation of NO and ROS production by AdiNOS transduced vascular cells through supplementation with L-Arg and BH4: implications for gene therapy of restenosis. Atherosclerosis 18 23958248
2011 LARG links histamine-H1-receptor-activated Gq to Rho-GTPase-dependent signaling pathways. Cellular signalling 17 22100544
2010 Photocytotoxicity and DNA cleavage activity of L-arg and L-lys Schiff base oxovanadium(IV) complexes having phenanthroline bases. Dalton transactions (Cambridge, England : 2003) 17 20563340
2015 ϒ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum. Cell death and differentiation 16 26292756
2012 Angiotensin II regulates the LARG/RhoA/MYPT1 axis in rat vascular smooth muscle in vitro. Acta pharmacologica Sinica 15 23123644
2013 CYLD regulates RhoA activity by modulating LARG ubiquitination. PloS one 14 23405219
2018 Arhgef12 drives IL17A-induced airway contractility and airway hyperresponsiveness in mice. JCI insight 13 30385725
2017 Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation. Scientific reports 13 28094782
2007 Effects of endogenous nitric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice. World journal of gastroenterology 13 18069768
2012 Supplement of L-Arg improves protective immunity during early-stage Plasmodium yoelii 17XL infection. Parasite immunology 12 22709481
2006 A functional Tyr1306Cys variant in LARG is associated with increased insulin action in vivo. Diabetes 12 16644711
2003 Characterization of leukemia-associated Rho guanine nucleotide exchange factor (LARG) expression during murine development. Cell and tissue research 12 14513355
2022 Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model. PLoS genetics 11 35675330
2021 Therapy-induced Deletion in 11q23 Leading to Fusion of KMT2A With ARHGEF12 and Development of B Lineage Acute Lymphoplastic Leukemia in a Child Treated for Acute Myeloid Leukemia Caused by t(9;11)(p21;q23)/KMT2A-MLLT3. Cancer genomics & proteomics 11 33419897
2015 Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1. Cellular signalling 10 26483157
2021 Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12). Small GTPases 9 34304710
2021 Enzymatic Cβ-H Functionalization of l-Arg and l-Leu in Nonribosomally Derived Peptidyl Natural Products: A Tale of Two Oxidoreductases. Journal of the American Chemical Society 9 34767710
2014 Jun kinase-induced overexpression of leukemia-associated Rho GEF (LARG) mediates sustained hypercontraction of longitudinal smooth muscle in inflammation. American journal of physiology. Cell physiology 9 24740538
2021 MiR-361-5p/abca1 and MiR-196-5p/arhgef12 Axis Involved in γ-Sitosterol Inducing Dual Anti-Proliferative Effects on Bronchial Epithelial Cells of Chronic Obstructive Pulmonary Disease. International journal of chronic obstructive pulmonary disease 8 34675500
2018 Inhibition of aggregation of physically modified rice proteins by isoconcentration of l-Arg and l-Glu. International journal of biological macromolecules 8 30244131
2015 Role of GABAB receptor and L-Arg in GABA-induced vasorelaxation in non-diabetic and streptozotocin-induced diabetic rat vessels. Iranian biomedical journal 8 25864813
2015 CAT-1 as a novel CAM stabilizes endothelial integrity and mediates the protective actions of L-Arg via a NO-independent mechanism. Journal of molecular and cellular cardiology 8 26283571
2022 Targeting ARHGEF12 promotes neuroblastoma differentiation, MYCN degradation, and reduces tumorigenicity. Cellular oncology (Dordrecht, Netherlands) 7 36520365
2021 Identification of KMT2A-ARHGEF12 fusion in a child with a high-grade B-cell lymphoma. Cancer genetics 7 34237703
2019 Reduction of blood pressure elevation by losartan in spontaneously hypertensive rats through suppression of LARG expression in vascular smooth muscle cells. Journal of the Formosan Medical Association = Taiwan yi zhi 7 30962047
2022 ArhGEF12 activates Rap1A and not RhoA in human dermal microvascular endothelial cells to reduce tumor necrosis factor-induced leak. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 6 35294066
2008 Degenerate specificity of PDZ domains from RhoA-specific nucleotide exchange factors PDZRhoGEF and LARG. Acta biochimica Polonica 6 18542831
1998 Effects of L-NAME and L-Arg on arterial blood pressure in normotensive and hypertensive streptozotocin diabetic rats. Acta physiologica, pharmacologica et therapeutica latinoamericana : organo de la Asociacion Latinoamericana de Ciencias Fisiologicas y [de] la Asociacion Latinoamericana de Farmacologia 4 9695876
2024 What is the Origin of the Regioselective C3-Hydroxylation of L-Arg by the Nonheme Iron Enzyme Capreomycin C? Chemistry (Weinheim an der Bergstrasse, Germany) 3 39190221
2014 The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling. Cell cycle (Georgetown, Tex.) 3 25485589
2020 Conserved Dynamic Mechanism of Allosteric Response to L-arg in Divergent Bacterial Arginine Repressors. Molecules (Basel, Switzerland) 2 32397647
2018 Prophylactic treatment of L-Arg improves malaria outcomes by regulating host immune responses during Plasmodium yoelii 17XL infection. Experimental parasitology 2 30266573
2012 Interactions of L-Arg with calf thymus DNA using neutral red dye as a fluorescence probe. Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy 2 22842133
1980 Biological studies of Chlorella pyrenoidosa (strain LARG-1) cultures grown under space flight conditions. Life sciences and space research 2 11971285
2025 METTL3 Promotes Cutaneous T-Cell Lymphoma Progression by Regulating ARHGEF12 Expression. International journal of molecular sciences 1 40332203
2025 The effect of L-Arg supplementation on L-Arg/NO metabolic and AMPK/ACC-1 signalling pathways in adipose cells (3T3 L1). Amino acids 1 40764680
2025 Comprehensive exome profiling identifies ARHGEF12 mutation as a driver in gastric cancer with ovarian metastasis. Theranostics 1 40860157
2025 Impact of KCl and L-Arg substitution on low salt beef patties: oxidative, textural, flavor, and microbial insights. Food chemistry 1 41092626
2025 Correction: Gan et al. METTL3 Promotes Cutaneous T-Cell Lymphoma Progression by Regulating ARHGEF12 Expression. Int. J. Mol. Sci. 2025, 26, 3640. International journal of molecular sciences 1 41373919
2010 [Effect of L-Arg on inflammatory reaction and nuclear factor-kappa B signal pathway in the acute lung injury in rats induced by lipopolysaccaride]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 1 20476576
2007 Genetic variants in the leukemia-associated Rho guanine nucleotide exchange factor (ARHGEF12) gene are not associated with T2DM and related parameters in Caucasians (KORA study). European journal of endocrinology 1 17766704
1998 [Changes of nitric oxide synthase in hypoxic pulmonary hypertension and the effect of L-arg and L-NAME on pulmonary circulation]. Zhonghua bing li xue za zhi = Chinese journal of pathology 1 11245006
2026 Solo regulates the localization and activity of LARG for actin cytoskeletal remodeling in cell-substrate adhesions. Molecular biology of the cell 0 41739636
2026 Variant-to-gene mapping identifies ARHGEF12 as a primary open-angle glaucoma effector gene operating within retinal ganglion cells. bioRxiv : the preprint server for biology 0 41929112
2025 Polymorphic variants of ABCA1, PMM2, and ARHGEF12 genes and the risk of glaucoma in an Iranian population. International journal of ophthalmology 0 40385107
2025 Integrative multi-omics and single-cell transcriptomics reveal ARHGEF12 driving chemoresistance in bladder cancer. Hereditas 0 41310897
2025 Phosphorylation at S1288 of leukemia associated RhoGEF (LARG/ARHGEF12) induces plasma membrane localization and promotes binding and activation of RhoA. The Journal of biological chemistry 0 41338458
2023 Probing mechanistic questions in the PLP- and O2-dependent l-Arg oxidases. Methods in enzymology 0 37245913
2013 [Effects of L-Arg on expression of PI3K and PKB in liver among low-birth-weight newborn rats]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 0 23965885
1997 [Effect of L-arg and SNP on pulmonary arterial pressure and vascular structural changes of chronically hypoxic rats]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 0 10453488
1997 [Activation of L-Arg: no pathway in canine brain by the damage from complete cerebral ischemia-reperfusion]. Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University 0 9868109