Affinage

ARHGEF6

Rho guanine nucleotide exchange factor 6 · UniProt Q15052

Length
776 aa
Mass
87.5 kDa
Annotated
2026-06-09
39 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGEF6 (alphaPIX/Cool-2) is a guanine nucleotide exchange factor for the Rac1 and Cdc42 Rho GTPases that couples integrin and growth-factor signaling to actin remodeling, governing cell spreading, migration, and neuronal morphogenesis (PMID:11017088, PMID:21989057). Its substrate selectivity is set by oligomeric state: the dimer is a Rac-specific GEF in which DH and PH domains from opposite monomers cooperate in trans, whereas the monomer activates both Cdc42 and Rac, with SH3-domain binding of PAK or Cbl required for engagement of GDP-loaded GTPase (PMID:15306850). ARHGEF6 sits at the center of a Cdc42-to-Rac cascade in which GTP-Cdc42 allosterically stimulates its Rac-GEF activity while GTP-Rac feedback-inhibits it (PMID:15649357). Upstream, it is activated by PI3-kinase downstream of growth-factor and integrin receptors (PMID:10523848) and is recruited into the integrin-linked kinase (ILK)–parvin scaffold through direct binding to beta-parvin and, in the kidney, alpha-parvin (PARVA) (PMID:12499396, PMID:15897874, PMID:36414417). ARHGEF6 acts on the actin cytoskeleton chiefly through PAK — which it can activate by both GEF-dependent and GEF-independent (purely physical) mechanisms — and through the PAK–LIMK1–cofilin axis and the GIT2 adaptor (PMID:10037684, PMID:18378701, PMID:33527537). Through these effectors it controls dendritic spine morphogenesis and synaptic plasticity, lymphocyte proliferation and immune-synapse formation, thymocyte migratory arrest, and hair-cell stereocilia maintenance (PMID:17105769, PMID:21989057, PMID:18378701, PMID:24591366, PMID:30333726). Its activity is tuned post-translationally by PKA/PKG and PKCθ phosphorylation and by c-Cbl–mediated ubiquitin-dependent degradation (PMID:26507661, PMID:25694429, PMID:25450678). Loss-of-function mutations cause X-linked intellectual disability (MRX46) and X-linked congenital anomalies of the kidney and urinary tract, the latter via failure to activate CDC42/RAC1 and loss of PARVA binding (PMID:11017088, PMID:36414417).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Establishing how alphaPIX engages the PAK kinase resolved whether it acts solely as an upstream activator or also as a direct effector scaffold.

    Evidence Co-expression and in vitro kinase assays with GEF-dead alphaPIX and GTPase-binding-deficient PAK1 mutants in COS-1 cells

    PMID:10037684

    Open questions at the time
    • Did not establish the in vivo balance between GEF-dependent and GEF-independent PAK activation
    • Physiological GTPase substrate in this context not pinned down
  2. 1999 Medium

    Placing alphaPIX downstream of PI3-kinase identified the upstream lipid-signaling input that activates its GEF activity following receptor stimulation.

    Evidence Co-IP with receptor complexes, in vivo GEF assays, and membrane-targeted PI3-kinase in cells and Xenopus mesoderm

    PMID:10523848

    Open questions at the time
    • Whether p85 binds alphaPIX directly or via PAK/Nck not resolved
    • Single lab
  3. 2000 High

    Linking ARHGEF6 loss-of-function to X-linked mental retardation established it as a disease gene and tied its GEF activity to cognition.

    Evidence X/21 translocation and intron mutation analysis in patients with RT-PCR showing exon 2 skipping

    PMID:11017088

    Open questions at the time
    • Cellular mechanism linking GEF loss to cognitive deficit not addressed at this stage
  4. 2003 High

    Identifying beta-parvin and ARHGEF7 binding partners placed ARHGEF6 within the integrin-associated adhesion machinery and showed disease mutations disrupt these interactions.

    Evidence Yeast two-hybrid, co-IP, GST pulldown, and immunofluorescence with disease-mutant ARHGEF6

    PMID:12499396

    Open questions at the time
    • Functional consequence of PARVB binding for GTPase output not yet tested
    • Role of ARHGEF7 heterodimerization unclear
  5. 2004 High

    Demonstrating that dimerization state dictates substrate selectivity explained how one GEF can be Rac-specific or dual-specific depending on context.

    Evidence Biochemical dimerization analysis, in vitro GEF assays, mutagenesis, and co-IP with PAK and Cbl

    PMID:15306850

    Open questions at the time
    • Cellular triggers controlling dimer/monomer equilibrium in vivo not defined
    • No structural model of the trans DH-PH arrangement
  6. 2004 Medium

    Mapping the integrin-ILK-parvin-alphaPIX axis and a GEF-independent calpain interaction showed alphaPIX has both catalytic and scaffolding roles in cell spreading.

    Evidence Yeast interaction screens, co-IP, GST pulldown, GEF-dead mutants, and calpain inhibition during spreading assays

    PMID:15005707 PMID:15611136

    Open questions at the time
    • Mechanism of the calpain-4 GEF-independent spreading cascade not fully defined
    • Single lab
  7. 2005 High

    Defining the Cdc42-to-Rac allosteric cascade and feedback inhibition established ARHGEF6 as a coincidence detector that integrates GTPase activation states.

    Evidence In vitro GEF assays with recombinant GTPases, binding studies, and DH-domain mutagenesis; ILK siRNA/inhibitor epistasis in mammary cells

    PMID:15649357 PMID:15897874

    Open questions at the time
    • In vivo prevalence of the cascade versus direct activation unknown
    • ILK-to-alphaPIX pathway tested in one cell type
  8. 2008 High

    Knockout studies in neurons and lymphocytes established ARHGEF6 as physiologically required for spine morphogenesis, synaptic plasticity, and immune function, identifying GIT2, PAK, and LFA-1 as effectors.

    Evidence Arhgef6 knockout mice with Golgi staining, electrophysiology, GTPase pull-downs, and immune-synapse assays; hippocampal slice siRNA with constitutively active PAK3 rescue

    PMID:17105769 PMID:18378701 PMID:21989057

    Open questions at the time
    • Cell-type-specific contributions versus systemic effects not fully separated
    • Direct GIT2 regulation mechanism not detailed
  9. 2015 Medium

    Phosphoregulation and c-Cbl-mediated degradation established how ARHGEF6 activity and abundance are dynamically controlled by signaling and the ubiquitin system.

    Evidence MS phosphosite mapping (S684, S225/S488), Phos-tag, 14-3-3 co-IP in platelets, PKCθ epistasis in T cells, and ubiquitination/proteasome assays with shRNA rescue in glioma

    PMID:18378701 PMID:25450678 PMID:25694429 PMID:26507661

    Open questions at the time
    • How each phosphosite alters dimer state or GEF catalysis biochemically not resolved
    • c-Cbl substrate selectivity for alphaPIX over betaPIX mechanism unclear
  10. 2021 High

    Pharmacological dissection in knockout T cells separated the PAK2-LIMK1-cofilin (speed) and CDC42 (turning) branches of ARHGEF6-controlled migration.

    Evidence Arhgef6 knockout T-cell migration assays with phospho-blotting and selective LIMK1/CDC42 inhibition; kindlin-2/phospho-alphaPIX-Rac1 co-IP in melanoma

    PMID:33527537 PMID:34321603

    Open questions at the time
    • Compensatory betaPIX upregulation complicates clean loss-of-function interpretation
    • Kindlin-2 interaction validated in one tumor system
  11. 2023 High

    Demonstrating that disease mutants fail to activate CDC42/RAC1 and lose PARVA binding established ARHGEF6 as a cause of X-linked CAKUT via the integrin-parvin-GTPase pathway.

    Evidence Exome sequencing of a CAKUT cohort, mutant ARHGEF6 GTPase/spreading/co-IP assays, 3D MDCK lumen assays, and Arhgef6-deficient mouse and Xenopus models

    PMID:36414417

    Open questions at the time
    • Tissue-specific basis of why kidney is affected not explained
    • Genotype-phenotype correlation across mutations limited
  12. 2026 Medium

    Identifying ARHGEF6 enrichment in the interneuron lineage extended its role to inhibitory circuit assembly via migration and survival control.

    Evidence Arhgef6 knockout mice and ARHGEF6-KO human iPSC organoids/assembloids with migration tracking, apoptosis, and growth-cone imaging (preprint)

    PMID:41889951

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Molecular effectors driving interneuron apoptosis not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dimer/monomer equilibrium, phosphorylation marks, and parvin/GIT scaffolding are integrated in real time to set tissue-specific GTPase output remains unresolved.
  • No structural model integrating regulatory inputs
  • Quantitative in vivo measurement of dimer state lacking
  • Mechanism distinguishing alphaPIX from betaPIX functions incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005929 cilium 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
ARHGEF7CBLFERMT2GIT2ILKPAK1PARVAPARVB
Complex memberships
ARHGEF6/GIT1/14-3-3 complexILK-parvin scaffold

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ARHGEF6 encodes a guanine nucleotide exchange factor (GEF) for Rho GTPases (Rac1/Cdc42); loss-of-function mutations (including a splice-site mutation causing skipping of exon 2 and deletion of 28 amino acids) cause X-linked mental retardation (MRX46), establishing ARHGEF6 as a disease gene whose GEF activity is required for normal cognitive function. Molecular analysis of X/21 translocation, intron mutation screening in patients, RT-PCR demonstrating preferential exon 2 skipping Nature genetics High 11017088
1999 alphaPIX stimulates PAK1 kinase activity through two distinct mechanisms: (1) an exchange-factor-dependent mechanism requiring both alphaPIX GEF activity and the physical interaction of alphaPIX with PAK1, and (2) an exchange-factor-independent mechanism mediated purely by physical binding of alphaPIX to PAK1, as shown by GEF-dead mutants still activating a GTPase-binding-deficient PAK1 mutant. Co-expression in COS-1 cells with kinase activity assays, in vitro kinase assay with GTPγS-loaded Cdc42, mutagenesis of PAK1 and alphaPIX The Journal of biological chemistry High 10037684
1999 alphaPIX is activated by PI3-kinase signaling downstream of PDGF and EphB2 receptors and integrin-induced pathways; alphaPIX forms a complex with the p85 regulatory subunit of PI3-kinase (either directly or via PAK/Nck), and membrane-targeted PI3-kinase or synthetic phosphoinositides augment alphaPIX GEF activity in vivo. Co-immunoprecipitation with receptor complexes, in vivo GEF activity assays, membrane-targeted PI3-kinase overexpression, Xenopus mesodermal cell spreading assay Oncogene Medium 10523848
2004 Cool-2/alphaPIX dimerization state determines GTPase substrate specificity: the dimeric form is a Rac-specific GEF (DH and PH domains from opposite monomers cooperate in trans to bind Rac-GDP), whereas the monomeric form acts as a GEF for both Cdc42 and Rac. Binding of PAK or Cbl to the SH3 domain of the monomer is required for functional interaction with GDP-bound Cdc42 or Rac. The Gβγ subunit complex, by interacting with PAK, stimulates dissociation of the Cool-2 dimer and activates its GEF activity for Cdc42. Biochemical dimerization analysis, in vitro GEF assays, mutagenesis, co-immunoprecipitation with PAK and Cbl The EMBO journal High 15306850
2005 Cool-2/alphaPIX mediates a Cdc42-to-Rac GTPase cascade: activated Cdc42 binds the DH domain of the Cool-2 dimer and allosterically enhances its association with GDP-bound Rac1, markedly stimulating Rac-GEF activity. Conversely, activated Rac binds Cool-2 and strongly inhibits its GEF activity, providing feedback inhibition. In vitro GEF activity assays with recombinant proteins, binding studies, domain mutagenesis Current biology : CB High 15649357
2003 ARHGEF6 physically interacts with beta-parvin (PARVB/affixin) via its N-terminal CH domain and C-terminal coiled-coil domain; both domains are required for PARVB binding. ARHGEF6 and PARVB co-localize at lamellipodia and ruffles in cells spreading on fibronectin. Disease-associated ARHGEF6 mutations (Δaa56-83 and Δaa396-776) abolish PARVB interaction. ARHGEF6 also heterodimerizes with ARHGEF7 (betaPIX) via the coiled-coil domain. Yeast two-hybrid, co-immunoprecipitation, GST pulldown, immunofluorescence co-localization, mutant analysis Human molecular genetics High 12499396
2004 Calpain 4 (the small subunit of mu- and m-calpain) is a novel binding partner of alphaPIX; interaction requires the SH3-DH-PH triple domain of alphaPIX. alphaPIX co-localizes with calpain and integrin-linked kinase in early integrin clusters during cell spreading. alphaPIX plays a dual role in integrin-dependent spreading: GEF activity drives protrusion formation, while a GEF-independent association with calpain 4 activates a distinct spreading cascade. CytoTrap yeast interaction system, co-immunoprecipitation, GST pulldown, immunofluorescence, overexpression of GEF-dead mutant (L386R/L387S), calpain inhibitor treatment The Journal of biological chemistry High 15611136
2005 ILK kinase activity is required upstream of alphaPIX for Rac and Cdc42 activation and actin cytoskeleton reorganization in mammary epithelial cells; ILK acts via its interaction with beta-parvin, which bridges to alphaPIX as the Rac/Cdc42-GEF. ILK siRNA knockdown, small-molecule ILK inhibitors, active ILK overexpression, Rac/Cdc42 activation assays (pull-down), cell spreading assays Oncogene Medium 15897874
2004 The first CH domain of affixin (beta-parvin) activates Cdc42 and Rac1 through alphaPIX; affixin and alphaPIX co-immunoprecipitate and co-localize at lamellipodia tips. A GEF-dead alphaPIX point mutant (L383R/L384S) dominantly inhibits the affixin CH1-induced Cdc42 activation, placing alphaPIX directly downstream of affixin in this integrin-ILK signaling pathway. Co-immunoprecipitation, immunofluorescence co-localization, dominant-negative GEF-dead mutant rescue experiment, GTPase activation assays Genes to cells : devoted to molecular & cellular mechanisms Medium 15005707
2006 ARHGEF6 localizes to dendritic spines (co-localizing with PSD95) and is required for normal spine morphogenesis; siRNA knockdown of ARHGEF6 in hippocampal slice cultures produces spine morphology defects that can be rescued by constitutively active PAK3 but not wild-type PAK3, placing ARHGEF6 upstream of PAK3 activation in the spine morphogenesis pathway. Transfection and immunofluorescence in hippocampal slice cultures, siRNA knockdown, constitutively active PAK3 rescue experiment Journal of cell science Medium 17105769
2011 In alphaPix/Arhgef6 knockout mice, hippocampal pyramidal neurons show increased dendritic length and spine density but loss of spine synapses; early-phase LTP is reduced and LTD is increased in CA1. Active Rac1 and Cdc42 (but not RhoA) are significantly reduced, directly linking ARHGEF6 GEF activity to Rac1/Cdc42 control of synaptic plasticity and cognitive function. Knockout mouse generation, Golgi-Cox staining, electrophysiology (LTP/LTD), behavioral testing, Rac1/Cdc42/RhoA activity pull-down assays Human molecular genetics High 21989057
2006 alphaPIX and PAK4 regulate podosome size and number in primary human macrophages; alphaPIX localizes to podosomes and its overexpression (including an SH3-deleted mutant) causes coalescence of podosomes, demonstrating a localized actin regulatory role that is independent of the alphaPIX SH3 domain. Immunofluorescence in primary macrophages, shRNA knockdown of PAK4, overexpression of alphaPIX wild-type and SH3-deleted mutant, quantification of podosome number and size Journal of cellular physiology Medium 16897755
2008 In alphaPIX knockout mice, mature lymphocyte numbers are reduced, antigen receptor-directed proliferation of T and B cells is diminished, and T-cell–B-cell conjugate formation is impaired. PAK recruitment and LFA-1 integrin recruitment to the immune synapse are defective in alphaPIX-null cells. GIT2 expression is reduced in both T and B cells lacking alphaPIX, revealing GIT2 as a downstream effector. alphaPIX knockout mouse analysis, flow cytometry, proliferation assays, immune synapse immunofluorescence, PAK/LFA-1 recruitment assays, western blotting for GIT2 Molecular and cellular biology High 18378701
2015 PKA and PKG phosphorylate ARHGEF6 at serine 684 in platelets, and this phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex, thereby modulating Rac1 activity downstream of prostacyclin/nitric oxide signaling. Mass spectrometry phosphoproteomics, Phos-tag gel electrophoresis, co-immunoprecipitation, PKA/PKG activation with pharmacological agents in platelets The Journal of biological chemistry Medium 26507661
2015 In IL-2-stimulated T cells, PKCθ phosphorylates alphaPIX at serines 225 and 488, and this phosphorylation is required for alphaPIX to activate Rac1, which in turn activates glycogen phosphorylase (PYGM), linking alphaPIX to a PKCθ/αPIX/Rac1/PYGM signaling pathway controlling T cell proliferation and migration. Directed mutagenesis of alphaPIX phosphorylation sites, pharmacological and genetic PKCθ inhibition/overexpression, Rac1 activation pull-down assay, PYGM activity assay in Kit225 T cells The Journal of biological chemistry Medium 25694429
2009 alphaPIX binds mutant huntingtin (muthtt) via its DH and PH domains (shown by deletion analysis and co-immunoprecipitation); alphaPIX overexpression enhances muthtt aggregation by inducing SDS-soluble muthtt-muthtt interactions, while alphaPIX knockdown attenuates muthtt aggregation. Co-immunoprecipitation, deletion analysis, co-localization studies, overexpression and siRNA knockdown with aggregation assays Journal of the neurological sciences Medium 19969308
2013 alphaPIX/Arhgef6 GEF activity promotes translocation of Golgi cisternae into developing dendrites of hippocampal neurons as a downstream component of reelin signaling; exchange-activity-deficient alphaPIX or dominant-negative Cdc42/Rac1 impairs dendritic Golgi positioning, and this defect is not rescued by reelin. Hippocampal neuron transfection with GEF-dead alphaPIX, dominant-negative GTPases, Golgi immunofluorescence, reelin treatment The European journal of neuroscience Medium 23406282
2012 alphaPIX (but not betaPIX) is specifically required for dendritogenesis and axonal branching in hippocampal neurons; siRNA silencing of alphaPIX hampers dendrite formation, and GIT2 (but not GIT1) knockdown mimics this phenotype, identifying alphaPIX and GIT2 as part of the same pathway in early neuronal differentiation. siRNA knockdown of alphaPIX and GIT isoforms, morphological analysis of hippocampal neurons, mass spectrometry identification of PIX isoforms Biology of the cell Medium 22554054
2014 c-Cbl functions as a ubiquitin E3 ligase that mediates proteasome-dependent degradation specifically of alphaPIX (but not betaPIX); loss of c-Cbl in glioma cells leads to alphaPIX accumulation, and alphaPIX depletion reduces glioma cell migration and invasion. Ubiquitination assays, proteasome inhibitor treatment, shRNA knockdown of alphaPIX in glioma cells, migration and invasion assays, shRNA-insensitive alphaPIX complementation Biochemical and biophysical research communications Medium 25450678
2015 alphaPIX acts as a bimodal regulator of EGFR trafficking: (1) alphaPIX sequesters c-Cbl from EGFR upon EGF stimulation, reducing EGFR ubiquitination and lysosomal degradation; (2) alphaPIX strongly promotes EGFR recycling to the cell surface via its GIT-binding domain, independently of c-Cbl interaction or alphaPIX exchange activity. EGF stimulation induces alphaPIX::c-Cbl complex formation, and both proteins decrease in level in a c-Cbl ubiquitin-ligase-activity-dependent manner. Co-immunoprecipitation, EGFR ubiquitination assays, EGFR surface recycling assays, domain-deletion mutant analysis (GIT-binding domain), quantitative trafficking assays PloS one Medium 26177020
2007 H. pylori CagA, upon translocation into gastric epithelial cells, physically interacts with alphaPIX; CagA phosphorylation by Src induces dephosphorylation of alphaPIX, which may modulate cytoskeletal changes through PAK. Immunoprecipitation with anti-CagA antibody, proteomic identification of alphaPIX, time-course co-IP during H. pylori infection Annals of the New York Academy of Sciences Low 17405911
2009 alphaPIX interaction with H. pylori CagA activates PAK1, ERK, and NF-κB signaling to induce IL-8 expression in gastric epithelial cells; siRNA knockdown of alphaPIX specifically inhibits these downstream signaling activations and IL-8 induction after CagA translocation (4 h post-infection) but not the early (1-2 h) CagA-independent phase. siRNA knockdown of alphaPIX in H. pylori-infected AGS cells, western blotting for PAK1/ERK/NF-κB phosphorylation, IL-8 ELISA/expression assay Scandinavian journal of gastroenterology Medium 19672789
2014 alphaPIX knockout thymocytes show greatly increased motility and altered morphology on ICAM-1, reduced ability to arrest in response to TCR stop signals, and defective positive selection (but not negative selection). These effects are largely independent of TCR proximal signaling, identifying alphaPIX as a regulator of thymocyte migration arrest linked to integrin-dependent scanning behavior. Knockout mouse analysis, 2D migration assays on ICAM-1, thymic cortex intravital imaging, ICAM-1-bead interaction assays, TCR signaling assays Journal of immunology Medium 24591366
2016 alphaPIX, acting downstream of the ILK-parvin axis, is required for prolactin-induced lactational differentiation of mammary epithelial cells; shRNA knockdown of alphaPIX prevents differentiation without disrupting focal adhesions, proliferation, or polarity, identifying alphaPIX as a differentiation-specific bifurcation point in β1-integrin-ILK signaling. shRNA knockdown of alphaPIX and parvins, ILK mutant expression that disrupts parvin binding, differentiation assays in mammary epithelial cells Journal of cellular physiology Medium 27019299
2018 ARHGEF6 is expressed in cochlear hair cell stereocilia and is required for stereocilia maintenance; CRISPR-Cas9 knockdown of Arhgef6 in mice causes progressive outer hair cell stereocilia deficits, hair cell loss, and hearing loss, with significantly decreased active CDC42 and RAC1, while synaptic density and mechanoelectrical transduction currents at P3 are unaffected. CRISPR-Cas9 knockdown mouse model, immunofluorescence of stereocilia, auditory brainstem response/DPOAE hearing tests, GTPase activation pull-down assays, electrophysiology (MET currents) Frontiers in molecular neuroscience High 30333726
2021 In Arhgef6-/- T cells, loss of ARHGEF6 leads to reduced PAK2 and LIMK1 phosphorylation and increased cofilin activation, causing increased migration speed and excessive cell turning; increased betaPIX (Arhgef7) expression correlates with defective Rac1 and CDC42 localization. Pharmacological LIMK1 inhibition in WT cells recapitulates increased speed but not turning, while CDC42 inhibition increases turning but not speed, dissecting two distinct downstream mechanisms. Knockout T cell migration assays on 2D surfaces, western blotting for PAK2/LIMK1/cofilin phosphorylation, pharmacological inhibition of LIMK1 and CDC42, Rac1/CDC42 localization imaging Journal of leukocyte biology High 33527537
2021 Kindlin-2 (FERMT2) binds specifically to phospho-alphaPIX (at S13) and Rac1, enhancing the exchange of GDP for GTP on Rac1 and activating downstream MAPK signaling in melanoma cells. Co-immunoprecipitation of kindlin-2 with p-alphaPIX(S13) and Rac1, Rac1-GTP pull-down assay, in vitro and in vivo tumor growth assays, siRNA knockdown Oncogene Medium 34321603
2023 Disease-associated hemizygous ARHGEF6 mutant proteins fail to activate CDC42/RAC1, do not induce lamellipodia formation, fail to stimulate PARVA-dependent cell spreading, and lose interaction with PARVA; these defects cause dysregulation of integrin-parvin-RAC1/CDC42 signaling leading to X-linked CAKUT. Arhgef6 deficiency in mouse and frog models recapitulates human CAKUT features. Exome sequencing in human CAKUT cohort, overexpression of WT vs. mutant ARHGEF6 in kidney cells with GTPase activation assays, lamellipodia/spreading assays, co-IP for PARVA interaction, 3D MDCK culture lumen formation, Arhgef6-deficient mouse and Xenopus models Journal of the American Society of Nephrology : JASN High 36414417
2015 miR-135a directly represses ARHGEF6 expression; enforced miR-135a expression in highly tumorigenic medulloblastoma cancer stem cells inhibits tumorigenesis by suppressing Arhgef6, establishing ARHGEF6 as a direct miR-135a target gene mediating tumorigenic potential. miRNA profiling, miR-135a overexpression in cancer stem cells with luciferase reporter or mRNA/protein assays, in vivo tumorigenesis assays Stem cells (Dayton, Ohio) Medium 25639612
2026 ARHGEF6 is selectively enriched in the inhibitory interneuron lineage during peak interneuron generation and migration; its loss in mice reduces cortical and hippocampal interneuron number, disrupts tangential migration, increases developmental apoptosis, and impairs morphological and electrophysiological maturation. ARHGEF6-knockout human iPSC-derived organoids and assembloids exhibit increased apoptosis, reduced neuronal output, disorganized growth cones, impaired neurite branching, and disrupted migratory dynamics, indicating a conserved early role in inhibitory circuit assembly. Arhgef6 knockout mice, cortical/hippocampal interneuron counting and migration tracking, electrophysiology, iPSC-derived cerebral organoids and assembloids from ARHGEF6-KO iPSCs, apoptosis assays, growth cone imaging bioRxivpreprint Medium 41889951

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nature genetics 281 11017088
1999 alphaPix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms. The Journal of biological chemistry 113 10037684
2005 The Cool-2/alpha-Pix protein mediates a Cdc42-Rac signaling cascade. Current biology : CB 106 15649357
2003 Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Human molecular genetics 104 12499396
2005 Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via alpha-PIX. Oncogene 99 15897874
1999 alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase. Oncogene 89 10523848
2011 Dysregulation of Rho GTPases in the αPix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits. Human molecular genetics 88 21989057
2004 Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix. The EMBO journal 74 15306850
2006 Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Journal of cell science 60 17105769
2018 Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice. Frontiers in molecular neuroscience 59 30333726
2006 PAK4 and alphaPIX determine podosome size and number in macrophages through localized actin regulation. Journal of cellular physiology 55 16897755
2005 Identification of histological markers for malignant glioma by genome-wide expression analysis: dynein, alpha-PIX and sorcin. Acta neuropathologica 49 16320026
2004 The first CH domain of affixin activates Cdc42 and Rac1 through alphaPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor. Genes to cells : devoted to molecular & cellular mechanisms 47 15005707
2008 AlphaPIX Rho GTPase guanine nucleotide exchange factor regulates lymphocyte functions and antigen receptor signaling. Molecular and cellular biology 40 18378701
2004 AlphaPIX associates with calpain 4, the small subunit of calpain, and has a dual role in integrin-mediated cell spreading. The Journal of biological chemistry 40 15611136
2015 miR-135a Inhibits Cancer Stem Cell-Driven Medulloblastoma Development by Directly Repressing Arhgef6 Expression. Stem cells (Dayton, Ohio) 38 25639612
2013 Reelin and the Cdc42/Rac1 guanine nucleotide exchange factor αPIX/Arhgef6 promote dendritic Golgi translocation in hippocampal neurons. The European journal of neuroscience 35 23406282
2015 Cyclic Nucleotide-dependent Protein Kinases Target ARHGAP17 and ARHGEF6 Complexes in Platelets. The Journal of biological chemistry 28 26507661
2015 Guanine nucleotide exchange factor αPIX leads to activation of the Rac 1 GTPase/glycogen phosphorylase pathway in interleukin (IL)-2-stimulated T cells. The Journal of biological chemistry 22 25694429
2012 Biochemical and functional characterisation of αPIX, a specific regulator of axonal and dendritic branching in hippocampal neurons. Biology of the cell 18 22554054
2016 The Integrin-Mediated ILK-Parvin-αPix Signaling Axis Controls Differentiation in Mammary Epithelial Cells. Journal of cellular physiology 16 27019299
2014 c-Cbl regulates αPix-mediated cell migration and invasion. Biochemical and biophysical research communications 16 25450678
2007 Interaction between the Helicobacter pylori CagA and alpha-Pix in gastric epithelial AGS cells. Annals of the New York Academy of Sciences 16 17405911
2009 alpha Pix enhances mutant huntingtin aggregation. Journal of the neurological sciences 14 19969308
2016 FGF-2 deficiency causes dysregulation of Arhgef6 and downstream targets in the cerebral cortex accompanied by altered neurite outgrowth and dendritic spine morphology. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 12 26970009
2021 Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway. Oncogene 11 34321603
2014 αPIX RhoGEF supports positive selection by restraining migration and promoting arrest of thymocytes. Journal of immunology (Baltimore, Md. : 1950) 11 24591366
2009 alphaPix interacts with Helicobacter pylori CagA to induce IL-8 expression in gastric epithelial cells. Scandinavian journal of gastroenterology 9 19672789
2001 The mouse Arhgef6 gene: cDNA sequence, expression analysis, and chromosome assignment. Cytogenetics and cell genetics 8 12063400
2021 Arhgef6 (alpha-PIX) cytoskeletal regulator signals to GTPases and Cofilin to couple T cell migration speed and persistence. Journal of leukocyte biology 7 33527537
2001 Characterization of ARHGEF6, a guanine nucleotide exchange factor for Rho GTPases and a candidate gene for X-linked mental retardation: mutation screening in Börjeson-Forssman-Lehmann syndrome and MRX27. American journal of medical genetics 6 11337747
2015 αPIX Is a Trafficking Regulator that Balances Recycling and Degradation of the Epidermal Growth Factor Receptor. PloS one 5 26177020
2001 Genomic structure of human alpha-pix, and variable deletions in a poly (T) tract in gastric cancer tissue. Cancer letters 5 11166917
2023 The pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma. Computers in biology and medicine 4 37058762
2023 Genetic Variants in ARHGEF6 Cause Congenital Anomalies of the Kidneys and Urinary Tract in Humans, Mice, and Frogs. Journal of the American Society of Nephrology : JASN 3 36414417
2023 Clinical implication and potential function of ARHGEF6 in acute myeloid leukemia: An in vitro study. PloS one 1 37027440
2023 Combined ARHGEF6 and Tumor Mutational Burden may serve as a potential biomarker for immunotherapy of lung adenocarcinoma. Heliyon 1 37600416
2026 ARHGEF6-dependent cytoskeletal regulation underlies a conserved program of forebrain interneuron development. bioRxiv : the preprint server for biology 0 41889951
2025 ARHGEF6 downregulation as a key mediator of tumor cell apoptosis in breast cancer. Oncology letters 0 40995140

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