Affinage

ARHGEF6

Rho guanine nucleotide exchange factor 6 · UniProt Q15052

Length
776 aa
Mass
87.5 kDa
Annotated
2026-04-28
39 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGEF6 (αPIX/Cool-2) is a guanine nucleotide exchange factor for Rac1 and Cdc42 that couples integrin, receptor tyrosine kinase, and heterotrimeric G-protein signaling to actin cytoskeleton remodeling, cell migration, and synaptic plasticity. The protein exists in a dimer–monomer equilibrium: the dimer acts as a Rac-selective GEF using DH-PH domains in trans, whereas the monomer acquires Cdc42-GEF activity requiring PAK or Cbl binding to its SH3 domain; GTP-Cdc42 allosterically stimulates Rac exchange activity while GTP-Rac feeds back to inhibit it, establishing a directional Cdc42→Rac cascade (PMID:15306850, PMID:15649357). Upstream, ARHGEF6 is activated by PI3-kinase and the ILK–β-parvin/α-parvin axis and is negatively regulated by PKA/PKG phosphorylation at S684 (enabling 14-3-3 binding) and by c-Cbl-mediated proteasomal degradation (PMID:10523848, PMID:15897874, PMID:26507661, PMID:25450678); downstream, it signals through PAK–LIMK1–Cofilin to control actin dynamics, dendritic spine morphogenesis, thymocyte migration arrest, hair cell stereocilia maintenance, and kidney epithelial polarity (PMID:17105769, PMID:33527537, PMID:30333726, PMID:36414417). Loss-of-function mutations in ARHGEF6 cause X-linked intellectual disability and congenital anomalies of the kidney and urinary tract (CAKUT) (PMID:11017088, PMID:36414417).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1999 High

    Establishing that ARHGEF6 is not merely a scaffold but an active GEF: αPIX stimulates PAK1 kinase activity through both exchange factor-dependent (requiring Cdc42/Rac GTP loading) and exchange factor-independent (direct PAK1 binding) mechanisms, revealing its dual mode of action on PAK.

    Evidence In vitro PAK1 kinase assays with recombinant αPIX and site-directed mutagenesis in COS-1 cells

    PMID:10037684

    Open questions at the time
    • Whether the GEF-independent PAK stimulation occurs in physiological contexts
    • Structural basis of the PAK-binding versus GEF-activating domains
  2. 1999 High

    Identifying the upstream activators of ARHGEF6: PI3-kinase, activated downstream of PDGF receptor, EphB2, and integrins, augments αPIX GEF activity, placing ARHGEF6 as a signal integrator linking receptor tyrosine kinases to Rho GTPases.

    Evidence Co-immunoprecipitation, in vivo GEF assays, membrane-targeted PI3-kinase overexpression, and Xenopus mesoderm spreading

    PMID:10523848

    Open questions at the time
    • Whether PI3-kinase lipid products directly bind ARHGEF6 PH domain or act indirectly
    • Quantitative contribution of each receptor system in vivo
  3. 2000 High

    Linking ARHGEF6 loss to human disease: identification of loss-of-function mutations causing X-linked intellectual disability established that ARHGEF6 GEF activity is essential for normal cognitive development.

    Evidence Molecular analysis of X/21 translocation, mutation screening, and RT-PCR splice analysis across multiple families

    PMID:11017088

    Open questions at the time
    • Which neuronal subtypes are most vulnerable to ARHGEF6 loss
    • Whether partial loss of function produces milder phenotypes
  4. 2003 High

    Placing ARHGEF6 within the integrin–ILK–parvin signaling axis: direct binding to β-parvin (PARVB) via the CH domain was mapped, MRX-associated mutations abolished this interaction, and ARHGEF6/ARHGEF7 heterodimerization via the coiled-coil domain was demonstrated.

    Evidence Yeast two-hybrid, reciprocal co-IP, GST pull-down, immunofluorescence co-localization, and disease-mutant domain mapping

    PMID:12499396

    Open questions at the time
    • Crystal structure of the CH domain–PARVB interface
    • Functional consequence of ARHGEF6/ARHGEF7 heterodimerization versus homodimerization
  5. 2004 High

    Resolving how oligomeric state dictates substrate specificity: the dimer is Rac-selective (using DH-PH in trans), while the monomer gains Cdc42-GEF activity dependent on SH3-domain occupancy by PAK or Cbl; Gβγ subunits promote dimer dissociation, activating Cdc42 exchange.

    Evidence In vitro GEF reconstitution, dimerization analysis, SH3 binding studies, and Gβγ reconstitution

    PMID:15306850

    Open questions at the time
    • In vivo evidence that dimer-to-monomer transition controls substrate switching
    • Structural basis for SH3-dependent unmasking of Cdc42 exchange activity
  6. 2004 High

    Identifying an additional integrin-proximal partner: αPIX interacts with calpain 4 via its SH3-DH-PH domains, revealing a GEF-independent role in integrin-dependent cell spreading distinct from Rac/Cdc42 activation.

    Evidence CytoTrap yeast two-hybrid, co-IP, immunofluorescence co-localization, and GEF-dead mutant dissection in spreading cells

    PMID:15611136

    Open questions at the time
    • Whether calpain 4 binding modulates ARHGEF6 GEF activity or vice versa
    • Physiological importance in tissues with high calpain activity
  7. 2005 High

    Establishing the directional GTPase cascade: GTP-Cdc42 allosterically stimulates ARHGEF6 Rac-GEF activity while GTP-Rac inhibits it, creating a Cdc42→ARHGEF6→Rac1 signal relay with built-in negative feedback.

    Evidence In vitro GEF assays with activated GTPase mutants and domain mutagenesis

    PMID:15649357

    Open questions at the time
    • Kinetic parameters of the allosteric activation in cells
    • Whether the feedback inhibition by Rac is relieved by specific co-factors in vivo
  8. 2005 High

    Connecting integrin signaling through the complete ILK→β-parvin→αPIX pathway: ILK activity was shown to be required for Rac/Cdc42 activation, mediated through β-parvin binding to ARHGEF6.

    Evidence ILK siRNA and pharmacologic inhibition, GTPase activation assays, and actin imaging in epithelial cells

    PMID:15897874

    Open questions at the time
    • Direct demonstration that ILK phosphorylation of β-parvin increases αPIX binding
    • Contribution of α-parvin versus β-parvin in different tissues
  9. 2006 High

    Defining ARHGEF6 function in synapse biology: αPIX localizes to dendritic spines and acts upstream of PAK3 to control spine morphogenesis, as shown by knockdown-induced spine defects rescued by constitutively active PAK3.

    Evidence siRNA in hippocampal slice cultures with constitutively active PAK3 rescue and PSD95 co-localization

    PMID:17105769

    Open questions at the time
    • Identity of the Rac1 versus Cdc42 arm mediating spine effects
    • Whether ARHGEF6 also regulates presynaptic terminals
  10. 2008 High

    Demonstrating an immune-system role: ARHGEF6 knockout mice revealed requirements for normal lymphocyte numbers, T–B cell conjugation, and PAK/LFA-1 recruitment to the immune synapse.

    Evidence Arhgef6 knockout mice with flow cytometry, proliferation assays, immune synapse imaging

    PMID:18378701

    Open questions at the time
    • Whether the immune defects are Rac- or Cdc42-dependent
    • Contribution to innate immune cell function
  11. 2011 High

    Providing in vivo proof that ARHGEF6 GEF activity toward Rac1/Cdc42 underlies synaptic plasticity and cognition: knockout mice showed reduced Rac1/Cdc42 activation, altered LTP/LTD, and impaired learning.

    Evidence Arhgef6 knockout mice with Golgi-Cox staining, electrophysiology, behavioral testing, and GTPase activation assays

    PMID:21989057

    Open questions at the time
    • Cell-type-specific contributions (excitatory vs. inhibitory neurons)
    • Whether pharmacologic Rac1 activation rescues cognitive deficits
  12. 2013 Medium

    Uncovering a role in organelle positioning: ARHGEF6 GEF activity promotes translocation of Golgi into developing dendrites downstream of reelin signaling, linking extracellular cues to intracellular organelle trafficking.

    Evidence Overexpression of WT and GEF-dead αPIX with reelin treatment and live Golgi imaging in hippocampal neurons

    PMID:23406282

    Open questions at the time
    • Mechanism by which Rac1/Cdc42 activation repositions Golgi
    • Whether Golgi mispositioning contributes to the cognitive deficits in knockout mice
  13. 2014 Medium

    Clarifying negative regulation: c-Cbl was identified as a ubiquitin E3 ligase that specifically targets αPIX for proteasomal degradation, providing a proteostatic control point for ARHGEF6 levels and downstream cell migration.

    Evidence Co-IP, ubiquitination assays, shRNA rescue in glioma cells

    PMID:25450678

    Open questions at the time
    • Ubiquitination sites on ARHGEF6
    • Whether c-Cbl-mediated degradation is signal-regulated or constitutive
  14. 2014 Medium

    Revealing a migration-arrest function in immune development: ARHGEF6-knockout thymocytes fail to arrest in response to TCR stop signals during positive selection, showing ARHGEF6 acts downstream of TCR to control integrin-dependent migration arrest.

    Evidence Arhgef6 knockout mice with 2D migration assays, flow cytometry, and TCR signaling analysis

    PMID:24591366

    Open questions at the time
    • Molecular link between TCR signal and ARHGEF6 activation
    • Whether this function extends to peripheral T cell arrest at antigen-presenting cells
  15. 2015 High

    Defining inhibitory phosphoregulation: PKA/PKG phosphorylate S684 to enable 14-3-3 binding, rearranging the ARHGEF6/GIT1 complex and reducing Rac1-GTP in platelets, while PKCθ phosphorylates S225/S488 in T cells to activate ARHGEF6 toward Rac1, revealing context-dependent kinase control.

    Evidence Phos-tag gels, mass spectrometry, co-IP in platelets; mutagenesis and pharmacologic/genetic PKCθ inhibition in T cells

    PMID:25694429 PMID:26507661

    Open questions at the time
    • Whether S684 and S225/S488 phosphorylation are mutually exclusive or cooperative
    • Structural consequence of 14-3-3 binding on GEF activity
  16. 2015 Medium

    Discovering a GEF-independent role in receptor trafficking: αPIX promotes EGFR recycling via its GIT-binding domain and sequesters c-Cbl from EGFR, reducing EGFR ubiquitination and degradation.

    Evidence Co-IP, EGFR ubiquitination and recycling assays, domain deletion analysis upon EGF stimulation

    PMID:26177020

    Open questions at the time
    • Whether this EGFR recycling function operates in vivo
    • Generalizability to other receptor tyrosine kinases
  17. 2018 High

    Extending the phenotypic spectrum to hearing: ARHGEF6 maintains cochlear hair cell stereocilia through Rac1/Cdc42 activation, with its loss causing progressive hair cell degeneration and hearing loss.

    Evidence CRISPR-Cas9 knockdown mice with ABR testing, scanning EM, and GTPase activation assays

    PMID:30333726

    Open questions at the time
    • Which downstream effector (PAK, LIMK, or other) mediates stereocilia maintenance
    • Whether hearing loss is amenable to postnatal intervention
  18. 2021 High

    Dissecting two separable downstream signaling arms: in T cells, ARHGEF6 controls migration speed via PAK2→LIMK1→Cofilin and turning behavior via Cdc42, as shown by pharmacologic separation of phenotypes in knockout cells.

    Evidence Arhgef6 knockout mice with LIMK1 and Cdc42 inhibitors, phosphorylation and GTPase localization analysis

    PMID:33527537

    Open questions at the time
    • Whether the two arms converge at the level of focal adhesion dynamics
    • Relevance of the speed-versus-turning dissociation in in vivo immune surveillance
  19. 2023 High

    Expanding disease associations to kidney development: disease-causing ARHGEF6 variants disrupt α-parvin binding, abolish Rac1/Cdc42 activation in kidney cells, and cause CAKUT in patients, mice, and frogs.

    Evidence Exome sequencing, WT versus mutant overexpression with co-IP and GTPase assays, 3D MDCK cultures, mouse and Xenopus knockouts

    PMID:36414417

    Open questions at the time
    • Which kidney cell type requires ARHGEF6 for normal morphogenesis
    • Whether PARVA- versus PARVB-binding mutations produce distinct renal phenotypes

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis of the dimer-to-monomer transition and its allosteric control in vivo; the cell-type-specific contributions (excitatory versus inhibitory neurons, specific immune subsets) that explain the pleiotropic phenotype; and whether ARHGEF6 GEF activity can be pharmacologically modulated to treat intellectual disability or CAKUT.
  • No high-resolution structure of full-length ARHGEF6 dimer or monomer
  • No pharmacologic activator or inhibitor of ARHGEF6 GEF activity
  • Cell-type-specific conditional knockouts not yet reported for most tissue phenotypes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8
Localization
GO:0005856 cytoskeleton 4 GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-1266738 Developmental Biology 6 R-HSA-168256 Immune System 4 GO:0005794 Golgi apparatus 1
Partners
ARHGEF7CBLGIT1GIT2PAK1PAK3PARVAPARVB
Complex memberships
αPIX/GIT1 complexαPIX/PAK complexαPIX/βPIX heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ARHGEF6 (alphaPIX/Cool-2) encodes a guanine nucleotide exchange factor for Rho GTPases (Rac1/Cdc42); loss-of-function mutations (including a splice-site mutation causing exon 2 skipping and deletion of 28 amino acids) cause X-linked mental retardation, establishing its role in neuronal function. Molecular analysis of X/21 translocation, mutation screening, RT-PCR splice analysis Nature genetics High 11017088
1999 AlphaPIX stimulates PAK1 kinase activity through both exchange factor-dependent mechanisms (requiring GEF activity and Cdc42/Rac) and exchange factor-independent mechanisms (requiring direct physical interaction with PAK1 via the PAK-binding domain); in vitro, recombinant alphaPIX enhances GTPγS-Cdc42-stimulated PAK1 activity in a binding-dependent manner. COS-1 cell co-expression with kinase assays, in vitro PAK1 kinase assay with recombinant alphaPIX, site-directed mutagenesis of PAK1 binding and GEF activity The Journal of biological chemistry High 10037684
1999 AlphaPIX is activated downstream of PDGF receptor, EphB2 receptor, and integrin-induced signaling through PI3-kinase; alphaPIX forms a complex with these receptors via PAK/Nck or directly with the p85 subunit of PI3-kinase, and membrane-targeted PI3-kinase augments alphaPIX GEF activity in vivo. Co-immunoprecipitation, in vivo GEF activity assays, membrane-targeted PI3-kinase overexpression, Xenopus mesoderm spreading assay Oncogene High 10523848
2003 ARHGEF6 directly interacts with beta-parvin (PARVB/affixin) via its N-terminal calponin homology (CH) domain and C-terminal coiled-coil domain; ARHGEF6 and PARVB co-localize at lamellipodia and ruffles in cells spreading on fibronectin; MRX-associated mutations abolish PARVB binding. ARHGEF6 also heterodimerizes with ARHGEF7 (betaPIX) via its coiled-coil domain. Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down, immunofluorescence co-localization, domain deletion analysis with disease mutants Human molecular genetics High 12499396
2004 Dimeric Cool-2/alphaPIX functions as a Rac-specific GEF, using DH and PH domains from opposing monomers in trans to bind Rac-GDP; monomeric Cool-2 gains GEF activity toward Cdc42 as well as Rac. Binding of PAK or Cbl to the SH3 domain of monomeric Cool-2 is required for functional interaction with GDP-bound Cdc42 or Rac. Betagamma subunits of heterotrimeric G proteins, by interacting with PAK, stimulate Cool-2 dimer dissociation and activate its Cdc42-GEF activity. In vitro GEF activity assays, biochemical dimerization analysis, domain mutagenesis, SH3 binding studies, betagamma subunit reconstitution experiments The EMBO journal High 15306850
2005 Activated Cdc42 binds to the DH domain of the Cool-2/alphaPIX dimer and allosterically enhances its association with GDP-bound Rac1, markedly stimulating Rac-GEF activity; activated Rac also binds Cool-2 but strongly inhibits its GEF activity—establishing a Cdc42→Cool-2→Rac GTPase cascade with feedback inhibition by Rac. In vitro GEF activity assays, biochemical binding studies, domain mutagenesis Current biology : CB High 15649357
2005 ILK activity is required for Rac and Cdc42 activation in epithelial cells; the ILK–beta-parvin interaction and downstream alphaPIX GEF activity mediate ILK-induced Rac activation, actin cytoskeleton reorganization, and cell spreading on fibronectin. ILK siRNA knockdown, small molecule ILK inhibitors, active ILK overexpression, GTPase activation assays, actin cytoskeleton imaging Oncogene High 15897874
2004 AlphaPIX interacts with calpain 4 (the small subunit of mu- and m-calpain) via its SH3-DH-PH triple domain; during integrin-dependent cell spreading alphaPIX co-localizes with calpains and beta1-integrin in early integrin clusters. AlphaPIX GEF activity promotes formation of cellular protrusions during spreading, while its GEF-independent association with calpain 4 promotes a separate cell-spreading pathway. CytoTrap yeast two-hybrid, co-immunoprecipitation, GST pull-down, immunofluorescence, overexpression of GEF-dead mutant (L386R/L387S), calpain inhibitors The Journal of biological chemistry High 15611136
2004 The first CH domain (CH1) of affixin (beta-parvin) activates Cdc42 and Rac1 through alphaPIX; affixin co-immunoprecipitates with alphaPIX and they co-localize at lamellipodia tips. A GEF-dead point mutant of alphaPIX (L383R/L384S) acts as dominant-negative and abolishes CH1-induced Cdc42 activation. Overexpression in MDCK cells, co-immunoprecipitation, immunofluorescence co-localization, dominant-negative GEF mutant Genes to cells : devoted to molecular & cellular mechanisms Medium 15005707
2006 ARHGEF6 localizes to dendritic spines in hippocampal neurons where it co-localizes with PSD95; siRNA knockdown of ARHGEF6 causes spine morphology abnormalities that are rescued by constitutively active PAK3 (but not wild-type PAK3), establishing that ARHGEF6 acts upstream of PAK3 to regulate spine morphogenesis. siRNA knockdown in hippocampal slice cultures, transfection/overexpression, immunofluorescence, constitutively active PAK3 rescue Journal of cell science High 17105769
2006 AlphaPIX and PAK4 regulate podosome size and number in primary human macrophages; overexpression of alphaPIX (full-length or SH3-deletion mutant) induces coalescence of podosomes, while PAK4 kinase activity modulates podosome size. Immunofluorescence, shRNA knockdown of PAK4, overexpression of alphaPIX wild-type and SH3-deletion mutant, biochemical fractionation Journal of cellular physiology Medium 16897755
2008 AlphaPIX is required for normal lymphocyte numbers, antigen receptor-directed T and B cell proliferation, and T cell–B cell conjugate formation; in its absence, recruitment of PAK and LFA-1 integrin to the immune synapse is impaired, and PAK phosphorylation and GIT2 expression are reduced. AlphaPIX knockout mice, flow cytometry, proliferation assays, immune synapse imaging, phosphorylation analysis Molecular and cellular biology High 18378701
2011 Loss of alphaPIX/Arhgef6 in mice causes increased dendritic length and spine density in hippocampal pyramidal neurons but an overall loss of spine synapses; early-phase LTP is reduced and LTD is increased in CA1; spatial and complex learning are impaired; active Rac1 and Cdc42 (but not RhoA) are significantly reduced, directly linking alphaPIX GEF activity toward Rac1/Cdc42 to synaptic plasticity and cognition. Arhgef6 knockout mouse, Golgi-Cox staining, electrophysiology (LTP/LTD), behavioral testing, Rac1/Cdc42 activation assays Human molecular genetics High 21989057
2012 AlphaPIX (but not betaPIX) is specifically required for dendritic branching and axonal branching in hippocampal neurons; GIT2 (but not GIT1) phenocopies alphaPIX knockdown, placing GIT2 in the same pathway as alphaPIX for early hippocampal neuron differentiation. siRNA knockdown, overexpression, mass spectrometry identification of brain isoforms, neuronal morphology analysis Biology of the cell Medium 22554054
2013 AlphaPIX/Arhgef6 GEF activity promotes translocation of Golgi cisternae into developing dendrites of hippocampal neurons as a downstream component of a reelin-modulated signaling pathway; exchange-activity-deficient alphaPIX or dominant-negative Cdc42/Rac1 impairs dendritic Golgi positioning that cannot be rescued by reelin. Overexpression of wild-type and GEF-dead alphaPIX, dominant-negative GTPases, reelin treatment, live imaging of Golgi in hippocampal neurons The European journal of neuroscience Medium 23406282
2015 PKA and PKG phosphorylate ARHGEF6 at serine 684 in platelets, which enables binding of 14-3-3 adaptor protein to the constitutive ARHGEF6/GIT1 complex; this PKA/PKG-driven rearrangement of the ARHGEF6 complex is linked to reduction of Rac1-GTP levels and platelet inhibition. Phos-tag gel electrophoresis, mass spectrometry, co-immunoprecipitation, PKA/PKG activation assays in platelets The Journal of biological chemistry High 26507661
2015 PKCθ phosphorylates alphaPIX at serines 225 and 488 in IL-2-stimulated T cells; this phosphorylation is required for alphaPIX to activate Rac1, which in turn activates glycogen phosphorylase muscle isoform (PYGM), constituting a PKCθ/αPIX/Rac1/PYGM signaling pathway controlling T cell proliferation and migration. Directed mutagenesis of phospho-serines, pharmacologic and genetic PKCθ inhibition, Rac1 and PYGM activity assays, IL-2-stimulated T cell cultures The Journal of biological chemistry Medium 25694429
2015 AlphaPIX promotes EGFR recycling to the cell surface via its GIT-binding domain (independent of GEF activity or c-Cbl binding); additionally, EGF stimulation induces alphaPIX::c-Cbl complex formation which sequesters c-Cbl from EGFR, reducing EGFR ubiquitination and lysosomal degradation; c-Cbl acts as ubiquitin E3 ligase that degrades alphaPIX itself. Co-immunoprecipitation, EGFR ubiquitination assays, EGFR recycling and degradation assays, domain deletion analysis, EGF stimulation experiments PloS one Medium 26177020
2014 c-Cbl is a ubiquitin E3 ligase that specifically targets alphaPIX (but not betaPIX) for proteasome-mediated degradation, negatively regulating alphaPIX-dependent cell migration and invasion; glioma cells lacking c-Cbl accumulate alphaPIX and show enhanced migration and invasion that is reversed by alphaPIX shRNA. Co-immunoprecipitation, ubiquitination assays, shRNA knockdown, cell migration and invasion assays Biochemical and biophysical research communications Medium 25450678
2018 ARHGEF6 is expressed in mouse cochlear hair cell stereocilia; CRISPR-Cas9 knockdown of Arhgef6 causes outer hair cell stereocilia deficits, progressive hair cell loss, and hearing loss; active CDC42 and RAC1 levels are dramatically decreased in knockdown mice, establishing that ARHGEF6 maintains stereocilia through RAC1/CDC42 activation. CRISPR-Cas9 knockdown mice, auditory brainstem response testing, scanning electron microscopy, Rac1/Cdc42 activation assays, immunofluorescence Frontiers in molecular neuroscience High 30333726
2009 AlphaPIX binds to both wild-type and mutant huntingtin via its DH and PH domains; alphaPIX accumulates in mutant huntingtin aggregates and overexpression enhances mutant huntingtin aggregation by inducing SDS-soluble htt–htt interactions; knockdown of alphaPIX attenuates mutant huntingtin aggregation. Co-immunoprecipitation, immunofluorescence co-localization, deletion analysis, overexpression and siRNA knockdown aggregation assays Journal of the neurological sciences Medium 19969308
2014 AlphaPIX supports thymocyte positive selection by restraining migration; αPIX-knockout thymocytes show increased motility on ICAM-1, fail to arrest in response to TCR stop signals, and interact less with ICAM-1-coated beads; TCR proximal signaling is normal, placing αPIX downstream of TCR in the context of migration arrest during positive selection. Arhgef6 knockout mice, two-dimensional migration assays, thymocyte development analysis by flow cytometry, TCR signaling analysis, bead interaction assay Journal of immunology Medium 24591366
2021 In Arhgef6-knockout T cells, PAK2 and LIMK1 phosphorylation are reduced, leading to hyperactivation of the actin-severing factor Cofilin, which increases migration speed; abnormal Rac1 and CDC42 activation/localization increases cell turning; pharmacologic LIMK1 inhibition recapitulates increased speed (but not turning), while Cdc42 inhibition recapitulates increased turning (but not speed), dissecting two downstream arms of ARHGEF6 action. Arhgef6 knockout mice, 2D migration assays, phosphorylation analysis (PAK2, LIMK1, Cofilin), pharmacologic LIMK1 and Cdc42 inhibition, GTPase localization imaging Journal of leukocyte biology High 33527537
2021 Kindlin-2 (FERMT2) binds specifically to phospho-αPIX (p-S13) and Rac1, promoting GDP-to-GTP exchange on Rac1 and stimulating the downstream MAPK pathway in melanoma cells. siRNA library screening, co-immunoprecipitation, Rac1 GTP-loading assay, MAPK pathway analysis, in vitro and in vivo tumor models Oncogene Medium 34321603
2023 Disease-causing hemizygous variants in ARHGEF6 result in loss of interaction with PARVA (alpha-parvin); mutant ARHGEF6 fails to increase active CDC42/RAC1 levels, impairs lamellipodia formation, and abolishes PARVA-dependent cell spreading in kidney cells; 3D MDCK cultures expressing mutant ARHGEF6 show reduced lumen formation and polarity defects; Arhgef6-deficient mice and Xenopus frogs develop CAKUT features. Exome sequencing, overexpression of WT vs. mutant ARHGEF6 in kidney cells, CDC42/RAC1 activation assays, co-immunoprecipitation, 3D MDCK culture, mouse and frog knockout models Journal of the American Society of Nephrology : JASN High 36414417
2026 ARHGEF6 is selectively enriched in the inhibitory interneuron lineage during peak interneuron generation/migration; its loss in mice reduces cortical and hippocampal interneuron numbers, disrupts tangential migration, increases developmental apoptosis, and impairs morphological and electrophysiological maturation; ARHGEF6-KO human iPSC-derived organoids and assembloids recapitulate these deficits with disorganized growth cones, impaired neurite branching, and disrupted migratory dynamics. Arhgef6 knockout mice, iPSC-derived organoids and assembloids, immunofluorescence, live migration imaging, electrophysiology, apoptosis assays 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 280 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 84 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 59 17105769
2018 Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice. Frontiers in molecular neuroscience 58 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
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
2008 AlphaPIX Rho GTPase guanine nucleotide exchange factor regulates lymphocyte functions and antigen receptor signaling. Molecular and cellular biology 39 18378701
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 34 23406282
2015 Cyclic Nucleotide-dependent Protein Kinases Target ARHGAP17 and ARHGEF6 Complexes in Platelets. The Journal of biological chemistry 27 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 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 The pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma. Computers in biology and medicine 3 37058762
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