Affinage

ARHGEF7

Rho guanine nucleotide exchange factor 7 · UniProt Q14155

Length
803 aa
Mass
90.0 kDa
Annotated
2026-06-09
19 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGEF7 (β-PIX) is a multidomain Rho-family guanine nucleotide exchange factor that activates Rac1 and Cdc42 to drive actin cytoskeletal remodeling, cell migration, and developmental morphogenesis (PMID:31754215, PMID:32188698). It nucleates membrane-associated signaling complexes: it forms a ternary complex with STIL and PAK1 at lamellipodia, where its loss diminishes PAK1 substrate phosphorylation, leading-edge Rac1 activity, and migration (PMID:31754215), and it is recruited with podocalyxin, EBP50, and ezrin into a complex that activates Rac1 (PMID:20395446). In podocytes, β-PIX is the predominant Cdc42 GEF, and its conditional loss causes proteinuria and glomerulosclerosis with reduced Cdc42 and YAP activity (PMID:32188698). Beyond canonical GEF output, ARHGEF7 also scaffolds the Hippo pathway in a GEF-independent manner, binding LATS kinase and YAP/TAZ to promote YAP/TAZ phosphorylation and cytoplasmic retention (PMID:25425573). During cytokinesis it acts downstream of Rac1 in opposition to the centralspindlin GAP CYK4 (PMID:22945935). In neuronal development it is required for axon formation acting upstream of TC10 rather than Cdc42 (PMID:29891904), and conditional loss in cerebellar granule cell precursors impairs proliferation, differentiation, and migration (PMID:41585483). ARHGEF7 engages LRRK2 as both a GEF and a phosphorylation substrate, linking it to growth-cone actin dynamics and Golgi vesicle recruitment (PMID:21048939, PMID:25500533), and it mediates actomyosin-driven exocytosis of Weibel-Palade bodies in endothelial cells, regulating septin ring and cofilin-dependent actin remodeling (PMID:42024489). Its abundance is controlled by KLHL2-mediated ubiquitin-proteasome degradation (PMID:33163274).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2010 Medium

    Established that ARHGEF7 physically and functionally couples to LRRK2, defining a reciprocal GEF/substrate relationship that situates β-PIX within Parkinson-relevant signaling.

    Evidence Co-IP, in vitro GTPase and kinase assays with recombinant proteins, and R1441C mutant binding tests

    PMID:21048939

    Open questions at the time
    • LRRK2 phosphorylation sites on ARHGEF7 not mapped
    • cellular consequence of the reciprocal modification not defined here
  2. 2010 Medium

    Showed ARHGEF7 transduces a transmembrane scaffold signal into Rac1 activation, placing it downstream of podocalyxin in a membrane complex.

    Evidence Co-IP of a podocalyxin-EBP50-ezrin-ARHGEF7 complex with Rac1 pulldown and rescue by podocalyxin re-expression

    PMID:20395446

    Open questions at the time
    • direct vs indirect ARHGEF7-podocalyxin contact not resolved
    • single-lab Co-IP
  3. 2012 High

    Positioned ARHGEF7 in the mitotic exit pathway, acting downstream of Rac1 in opposition to the centralspindlin GAP CYK4 during cytokinesis.

    Evidence Genetic epistasis: siRNA depletion of ARHGEF7/PAK1 rescuing CYK4 GAP-mutant cytokinesis defects with live-cell imaging

    PMID:22945935

    Open questions at the time
    • spatial regulation of ARHGEF7 at the equator not defined
    • GEF activity vs scaffolding contribution not separated
  4. 2013 Medium

    Linked the ARHGEF7-LRRK2 relationship to a specific cellular process, growth-cone actin regulation, via mislocalization upon LRRK2 loss.

    Evidence LRRK2 knockdown in primary hippocampal neurons with ARHGEF7/TPM4 immunofluorescence and neurite morphology analysis

    PMID:24075941

    Open questions at the time
    • mechanism of ARHGEF7 recruitment to growth cones unknown
    • direct effect on Rac/Cdc42 at growth cones not measured
  5. 2014 High

    Revealed a GEF-independent function: ARHGEF7 scaffolds LATS-YAP/TAZ to promote Hippo signaling, decoupling part of its activity from nucleotide exchange.

    Evidence Reciprocal Co-IP, phosphorylation assays, shRNA knockdown, and GEF-dead mutant rescue in breast cancer cells

    PMID:25425573

    Open questions at the time
    • structural basis of LATS/YAP binding unmapped
    • relationship to its actin/Rac functions unresolved
  6. 2014 Medium

    Connected ARHGEF7 binding to LRRK2 phosphorylation state and Golgi vesicle recruitment, adding a membrane-trafficking dimension.

    Evidence siRNA kinome screen, LRRK2 phosphorylation assays, Co-IP under phospho-modulating conditions, and TGN46 localization

    PMID:25500533

    Open questions at the time
    • functional output of Golgi-associated ARHGEF7 not defined
    • single-lab study
  7. 2018 High

    Defined an essential developmental role in axon formation and identified TC10, not Cdc42, as the relevant downstream GTPase in cortical neurons.

    Evidence Arhgef7 shRNA knockdown in vitro and in vivo with constitutively active TC10 vs Cdc42 rescue

    PMID:29891904

    Open questions at the time
    • direct GEF activity toward TC10 not biochemically demonstrated here
    • upstream cue selecting TC10 unknown
  8. 2019 High

    Resolved the lamellipodial migration machinery into a STIL-ARHGEF7-PAK1 ternary complex required for leading-edge Rac1 activation.

    Evidence Co-IP of the ternary complex with reciprocal siRNA knockdowns, Rac1 activity, PAK1 substrate phosphorylation, and migration assays

    PMID:31754215

    Open questions at the time
    • how STIL is recruited to the complex unknown
    • stoichiometry/assembly order undefined
  9. 2020 High

    Established β-PIX as the principal podocyte Cdc42 GEF whose loss causes glomerular disease through reduced Cdc42 and YAP-dependent survival signaling.

    Evidence BioID proximity ligation, podocyte-specific conditional KO mice, Cdc42 activity and YAP readouts

    PMID:32188698

    Open questions at the time
    • link between Cdc42 activity and YAP survival signaling mechanistically incomplete
    • whether the Hippo-scaffolding function operates here not tested
  10. 2020 Medium

    Identified post-translational control of ARHGEF7 abundance via KLHL2-directed ubiquitin-proteasome degradation.

    Evidence Co-IP, ubiquitination assay, proteasome inhibition, and Kelch-domain mapping

    PMID:33163274

    Open questions at the time
    • physiological signals regulating KLHL2 targeting unknown
    • single-lab study
  11. 2024 Medium

    Extended ARHGEF7 isoform function to neuritogenesis and cortical lamination via Rac1 activation.

    Evidence Rac1 pulldown in β-PIX-d-overexpressing neurons plus in utero electroporation and layer-marker analysis

    PMID:39568178

    Open questions at the time
    • isoform-specific mechanism vs canonical β-PIX not dissected
    • loss-of-function not tested
  12. 2025 High

    Demonstrated a requirement for ARHGEF7 in cerebellar granule cell precursor proliferation, differentiation, and migration in vivo.

    Evidence Conditional KO mice with histology, BrdU proliferation, and migration assays

    PMID:41585483

    Open questions at the time
    • downstream GTPase(s) in GCPs not identified
    • molecular targets coupling ARHGEF7 to proliferation unclear
  13. 2025 Medium

    Linked ARHGEF7 to neuroprotection, showing it counters β-amyloid toxicity and supports synaptic growth and cognition through Wnt signaling.

    Evidence Viral overexpression/knockdown in mPFC neurons in vivo, transcriptomics, Wnt pathway assays, behavioral and dendritic analyses

    PMID:40598577

    Open questions at the time
    • mechanistic connection between ARHGEF7 and Wnt activation undefined
    • single-lab study
  14. 2026 High

    Established ARHGEF7 as the actomyosin driver of Weibel-Palade body exocytosis, regulating septin and cofilin during the post-fusion actin ring.

    Evidence siRNA depletion with live-cell GFP-VWF secretion imaging, truncated-domain rescue, and actomyosin ring kinetics

    PMID:42024489

    Open questions at the time
    • GTPase target driving the WPB actomyosin ring not pinned down
    • how full-length requirement relates to GEF vs PAK domains unresolved
  15. 2026 Medium

    Identified a redox post-translational switch, S-glutathionylation at C312, that potentiates ARHGEF7 GEF activity toward Rac1 to promote invasion.

    Evidence Site-specific glutathionylation and in vitro nucleotide exchange assays with C312 mutants plus downstream signaling and invasion readouts (preprint)

    PMID:42146387

    Open questions at the time
    • preprint, single lab, awaits peer review
    • in vivo relevance of C312 glutathionylation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARHGEF7's GEF activity, multivalent scaffolding (PAK1/STIL, LATS/YAP), and redox/ubiquitin regulation are integrated and selected among distinct GTPase outputs (Rac1, Cdc42, TC10) in a context-specific manner remains unresolved.
  • no structural model coordinating GEF vs scaffold modes
  • determinants of GTPase selectivity across tissues unknown
  • regulatory inputs governing complex assembly not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CDC42KLHL2LATS1LRRK2PAK1RAC1STILYAP1
Complex memberships
STIL-ARHGEF7-PAK1 complexpodocalyxin-EBP50-ezrin-ARHGEF7 complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 CYK4 (the GAP subunit of centralspindlin) negatively regulates Rac1 activity at the cell equator during anaphase, and depletion of ARHGEF7 (together with PAK1) rescues cytokinesis defects caused by CYK4 GAP mutants, placing ARHGEF7 downstream of Rac1 and in opposition to CYK4 during mitotic exit. Genetic epistasis (siRNA depletion of ARHGEF7/PAK1 rescuing CYK4 GAP mutant phenotype), immunofluorescence for vinculin, live-cell imaging The Journal of cell biology High 22945935
2010 ARHGEF7 (β-PIX) physically interacts with LRRK2 and CDC42 in vitro and in vivo; ARHGEF7 acts as a GEF for LRRK2, increasing its GTPase activity; in turn, LRRK2 phosphorylates ARHGEF7 at previously unknown sites in vitro; the pathogenic R1441C LRRK2 mutant shows reduced binding to ARHGEF7. Co-immunoprecipitation (in vitro and in vivo), in vitro GTPase assay with recombinant proteins, in vitro kinase assay, binding assay with R1441C mutant PloS one Medium 21048939
2013 ARHGEF7 is mislocalized and dysregulated at growth cones in LRRK2-knockdown primary hippocampal neurons, which display enhanced neurite branching and an increased number of growth cones, indicating ARHGEF7 cooperates with LRRK2 to regulate actin polymerization at growth cones. LRRK2 knockdown in primary hippocampal neurons (LRRK2 KD animals), immunofluorescence for ARHGEF7 and TPM4 at growth cones, neurite morphology analysis Biochimica et biophysica acta Medium 24075941
2014 CK1α-mediated phosphorylation of LRRK2 modulates LRRK2 recruitment to TGN46-positive Golgi-derived vesicles through differential interaction with ARHGEF7, linking ARHGEF7 to Golgi maintenance downstream of LRRK2 phosphorylation. siRNA kinome screen, LRRK2 phosphorylation assays, Co-IP of LRRK2 with ARHGEF7 under phospho-modulating conditions, subcellular fractionation/immunofluorescence for TGN46 Nature communications Medium 25500533
2014 ARHGEF7 (βPix) binds both LATS kinase and YAP/TAZ and promotes LATS-mediated phosphorylation of YAP/TAZ in a GEF-independent manner, acting as a positive regulator of the Hippo pathway downstream of cell density sensing and actin cytoskeletal rearrangements; loss of βPix reduces YAP/TAZ phosphorylation and promotes their nuclear localization. Co-IP of βPix with Lats and Yap/Taz, phosphorylation assays, shRNA knockdown with YAP/Taz phosphorylation and nuclear localization readouts, GEF-dead mutant rescue experiments, overexpression in breast cancer cell lines The EMBO journal High 25425573
2010 ARHGEF7 is recruited into a complex with podocalyxin, ERM-binding phosphoprotein 50 (EBP50), and ezrin; this complex activates Rac1, and podocalyxin knockdown reduces Rac1 activity while podocalyxin overexpression increases it in a manner dependent on ARHGEF7. Co-immunoprecipitation demonstrating podocalyxin-EBP50-ezrin-ARHGEF7 complex, siRNA knockdown of podocalyxin with Rac1 activity assay (pulldown), rescue by podocalyxin re-expression The American journal of pathology Medium 20395446
2018 Arhgef7 is required for axon formation during cortical development; loss of Arhgef7 abolishes axons in cultured neurons and in the developing cortex; Arhgef7 functions upstream of TC10 (not Cdc42) in this context, as active TC10 rescues Arhgef7-knockdown axon loss whereas active Cdc42 does not. Arhgef7 shRNA knockdown in cortical neurons and in vivo, rescue with constitutively active TC10 or Cdc42, axon morphology quantification Scientific reports High 29891904
2019 STIL forms a ternary complex with ARHGEF7 and PAK1 and co-localizes with them at lamellipodia; ARHGEF7 knockdown diminishes STIL and PAK1 accumulation in membrane ruffles, reduces PAK1 substrate phosphorylation, and attenuates cortical actin remodeling; STIL or ARHGEF7 knockdown impedes cell migration and Rac1 activity at the leading edge. Co-IP demonstrating STIL-ARHGEF7-PAK1 ternary complex, siRNA knockdown of STIL and ARHGEF7, Rac1 activity assay, immunofluorescence of lamellipodial localization, PAK1 substrate phosphorylation assay, migration assay Oncogene High 31754215
2020 ARHGEF7 (β-PIX) is the predominant GEF for Cdc42 in podocytes (identified by BioID proximity ligation); podocyte-specific β-PIX knockout mice develop proteinuria and glomerulosclerosis with reduced Cdc42 activity; loss of β-PIX promotes podocyte apoptosis mediated by reduced activity of the prosurvival transcriptional regulator YAP. BioID proximity ligation assay identifying β-PIX-Cdc42 interaction, conditional KO mouse (β-PIX flox × Podocin-Cre), shRNA knockdown in cultured podocytes, Cdc42 activity assay, YAP activity measurement Journal of the American Society of Nephrology : JASN High 32188698
2020 KLHL2 E3 ubiquitin ligase physically interacts with ARHGEF7 via its Kelch domain and promotes ARHGEF7 degradation through the ubiquitin-proteasome pathway. Co-IP of ARHGEF7 with KLHL2, ubiquitination assay, proteasome inhibitor treatment, domain mapping (Kelch domain deletion), loss-of-function knockdown assays American journal of cancer research Medium 33163274
2025 Arhgef7 is expressed in granule cell precursors (GCPs); conditional knockout of Arhgef7 in GCPs causes cerebellar hypoplasia, impaired GCP proliferation, delayed differentiation, and defects in both tangential and radial migration of GCPs. Conditional knockout mice (Arhgef7 cKO in GCPs), histology, BrdU proliferation assay, cell migration assays, cerebellar morphology analysis iScience High 41585483
2026 ARHGEF7 (β-PIX) is required for actomyosin-mediated exocytosis of Weibel-Palade bodies (WPBs) in endothelial cells; β-PIX depletion reduces VWF secretion, impairs WPB fusion events, prolongs VWF release kinetics post-fusion, and delays exocytic actomyosin ring kinetics; the PAK-interacting and GEF domains mediate cytoskeletal remodeling, but full-length β-PIX is required for VWF secretion rescue; β-PIX regulates septin ring formation and cofilin-mediated actin remodeling during actomyosin ring function. siRNA depletion, live-cell imaging of GFP-VWF secretion, truncated domain rescue experiments, actomyosin ring kinetics imaging, septin and cofilin localization assays Molecular biology of the cell High 42024489
2026 ARHGEF7 is S-glutathionylated at the conserved C312 residue in its PH domain; C312 glutathionylation enhances ARHGEF7 binding to Rac1, increases Rac1 membrane/lamellipodia recruitment, accelerates GDP-GTP exchange rate, and activates Rac1-PAK1-LIMK1 and MEK1 signaling to promote cancer cell migration and invasion. Site-specific S-glutathionylation assay at C312, Rac1 binding assay, nucleotide exchange rate assay (in vitro GEF assay), immunofluorescence of Rac1 localization, PAK1/LIMK1/MEK1 phosphorylation assays, migration/invasion assays with C312 mutants bioRxivpreprint Medium 42146387
2024 β-PIX-d, an isoform of ARHGEF7, activates Rac1 and promotes neuritogenesis in primary cortical neurons; overexpression in the embryonic neocortex causes neuronal clustering and misplacement of layer V-VI neurons. Rac1 pulldown assay in β-PIX-d-overexpressing neurons, in utero electroporation, immunofluorescence with TuJ1 and layer-specific markers, primary cortical cultures Experimental neurobiology Medium 39568178
2025 Arhgef7 overexpression in mPFC neurons protects cortical neurons from β-amyloid toxicity by activating the Wnt signaling pathway, and promotes dendritic and synaptic growth; knockdown of Arhgef7 in mPFC neurons selectively impairs neuronal processes and spatial cognition. Viral overexpression and shRNA knockdown in mPFC neurons in vivo, transcriptomics, β-amyloid-exposed cultured forebrain neurons, Wnt pathway activity assays, behavioral tests, dendritic morphology analysis Alzheimer's research & therapy Medium 40598577

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 CYK4 inhibits Rac1-dependent PAK1 and ARHGEF7 effector pathways during cytokinesis. The Journal of cell biology 90 22945935
2014 Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. Nature communications 87 25500533
2010 Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7. The American journal of pathology 80 20395446
2010 ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2. PloS one 54 21048939
2013 LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4. Biochimica et biophysica acta 51 24075941
2014 Arhgef7 promotes activation of the Hippo pathway core kinase Lats. The EMBO journal 33 25425573
2018 The guanine nucleotide exchange factor Arhgef7/βPix promotes axon formation upstream of TC10. Scientific reports 30 29891904
2018 ARHGEF7 promotes metastasis of colorectal adenocarcinoma by regulating the motility of cancer cells. International journal of oncology 29 30132516
2019 Indispensable role of STIL in the regulation of cancer cell motility through the lamellipodial accumulation of ARHGEF7-PAK1 complex. Oncogene 18 31754215
2020 ARHGEF7 (β-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular Function. Journal of the American Society of Nephrology : JASN 17 32188698
2021 Three PilZ Domain Proteins, PlpA, PixA, and PixB, Have Distinct Functions in Regulation of Motility and Development in Myxococcus xanthus. Journal of bacteriology 8 33875546
2020 Ubiquitin ligase KLHL2 promotes the degradation and ubiquitination of ARHGEF7 protein to suppress renal cell carcinoma progression. American journal of cancer research 7 33163274
2018 Generalized epilepsy and mild intellectual disability associated with 13q34 deletion: A potential role for SOX1 and ARHGEF7. Seizure 6 29734022
2025 Arhgef7 as a key target for enriched environment rescuing spatial cognitive deficits and anxiety-like behaviors in a mouse model of Alzheimer's disease following early social isolation. Alzheimer's research & therapy 2 40598577
2018 Characterization of the pixB gene in Xenorhabdus nematophila and discovery of a new gene family. Microbiology (Reading, England) 2 29498622
2024 β-PIX-d, a Member of the ARHGEF7 Guanine Nucleotide Exchange Factor Family, Activates Rac1 and Induces Neuritogenesis in Primary Cortical Neurons. Experimental neurobiology 1 39568178
2026 Endothelial β-PIX (ARHGEF7) supports actomyosin mediated expulsion of VWF through dynamic reorganization of the cytoskeleton. Molecular biology of the cell 0 42024489
2026 ARHGEF7 S-glutathionylation promotes cancer cell migration through Rac1 activation. bioRxiv : the preprint server for biology 0 42146387
2025 Arhgef7 is essential for granule cell precursor proliferation and migration during cerebellum development. iScience 0 41585483

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