Affinage

VAV3

Guanine nucleotide exchange factor VAV3 · UniProt Q9UKW4

Length
847 aa
Mass
97.8 kDa
Annotated
2026-04-28
91 papers in source corpus 38 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VAV3 is a tyrosine phosphorylation-activated guanine nucleotide exchange factor (GEF) for Rho-family GTPases that transduces signals from diverse receptor tyrosine kinases and immune receptors to drive actin cytoskeletal remodeling, cell migration, and cytokinesis. In its unphosphorylated state, interdomain contacts between the calponin-homology/acidic region and the catalytic DH-PH core maintain an autoinhibited closed conformation; phosphorylation by Syk, Src-family kinases, or receptor tyrosine kinases (EGFR, ERBB4, EphA2, M-CSF-R) induces global conformational opening that activates exchange on RhoA, Rac1, RhoG, Cdc42, and Rap1, coupling to downstream effectors including PAK, PI3K-Akt, NF-κB, and PLCγ2 in context-dependent ways (PMID:10523675, PMID:15775967, PMID:15711558, PMID:29858212). Beyond its cytoplasmic GEF role, VAV3 localizes to the nucleus through a PH domain-dependent mechanism where it functions as a GEF-independent coactivator of androgen and estrogen receptors at target gene chromatin, and in leukemic cells interacts with PRC1 components (Bmi1, Ring1b) to regulate H2AK119 ubiquitination and self-renewal gene repression via nuclear Rac activation (PMID:21765461, PMID:35650206, PMID:16384856). In vivo, Vav3 deficiency causes sympathetic hyperactivity with hypertension, impaired osteoclast resorption, cerebellar developmental defects, defective myelination, and disrupted endothelial barrier integrity, reflecting its broad requirement for Rho GTPase-dependent cytoskeletal control across tissues (PMID:16767097, PMID:15711558, PMID:20089829, PMID:30450647, PMID:29858212).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Establishing VAV3 as a Rho-family GEF resolved its catalytic identity: the DH domain catalyzes GDP/GTP exchange on RhoA, RhoG, and Rac1, the CH domain is autoinhibitory, and constitutively active VAV3 drives stress fibers, lamellipodia, and cytokinesis defects via its central DH-PH-ZF region.

    Evidence In vitro nucleotide exchange assays with domain mutants, co-precipitation with nucleotide-free GTPases, actin cytoskeleton and multinucleation imaging in transfected cells

    PMID:10523675

    Open questions at the time
    • Structural basis of CH-domain autoinhibition not yet resolved at atomic level
    • Relative substrate preference among RhoA/Rac1/RhoG in physiological contexts undefined
    • In vivo relevance of cytokinesis regulation not tested
  2. 2000 High

    Demonstrating that multiple receptor tyrosine kinases (EGFR, Ros, IR, IGFR) phosphorylate and associate with VAV3 established it as a convergence node linking growth factor signaling to Rho GTPase activation.

    Evidence Co-immunoprecipitation and GST-pulldown with stimulated receptors, GTPase-binding domain assays for Rac1/Cdc42/RhoA activation

    PMID:11094073

    Open questions at the time
    • Which specific tyrosines on VAV3 are phosphorylated by each receptor not mapped
    • Whether all receptor interactions are direct or adaptor-mediated not resolved
  3. 2002 High

    Multiple studies defined downstream pathway branching: VAV3 activates PI3K-Akt for transformation and survival, regulates cytokinesis through RhoA requiring Y173 phosphorylation, sustains BCR-induced PIP3/Ca²⁺/JNK via Rac1, and is relieved from autoinhibition by APS adaptor binding to the CH domain.

    Evidence Cell-cycle synchronization with Y173 mutants and RhoA epistasis; B-cell KO with SHIP rescue; PI3K/MAPK inhibitors with focus/colony assays; APS co-IP with domain mapping and focus formation

    PMID:11805146 PMID:11884391 PMID:11917103 PMID:12400014

    Open questions at the time
    • Whether APS-mediated relief of autoinhibition operates in non-transformed cells unknown
    • Relative contribution of PI3K vs. direct GTPase pathways to transformation not quantified
  4. 2004 High

    Genetic redundancy between Vav1 and Vav3 in platelet GPVI-PLCγ2 signaling revealed that VAV3 participates in hemostatic signaling beyond lymphocytes.

    Evidence Vav1/Vav3 single and double KO platelets with GPVI stimulation, PLCγ2 phosphorylation, and aggregation assays

    PMID:15456756

    Open questions at the time
    • Whether Vav3 contributes to GPVI signaling independently of Vav1 remains unclear
    • GTPase substrate utilized in platelet context not identified
  5. 2005 High

    A suite of 2005 studies resolved the structural basis of activation, identified tissue-specific physiological roles, and uncovered a GEF-independent nuclear function: single-particle EM showed phosphorylation-induced global conformational opening; Vav3 KO osteoclasts revealed Syk-dependent actin/resorption defects; PI3K-Rac1 positive feedback was demonstrated in neurite outgrowth; TCR signaling required SLP-76 binding; and VAV3 was found to coactivate the androgen receptor through a PH domain-dependent, GEF-independent mechanism.

    Evidence Single-particle EM of three conformational states; Vav3 KO mice with osteoclast Syk epistasis; FRET biosensors and RNAi in PC12 cells; T-cell signaling in kinase/adaptor-deficient lines; AR reporter assays with domain/GEF-dead mutants

    PMID:15708849 PMID:15711558 PMID:15728722 PMID:15775967 PMID:16384856

    Open questions at the time
    • Atomic-resolution structure of full-length phosphorylated VAV3 not available
    • How PH domain mediates AR coactivation mechanistically unknown
    • Whether nuclear and cytoplasmic VAV3 pools are independently regulated not established
  6. 2006 High

    VAV3's DH domain was shown to mediate AR coactivation through PI3K-Akt, while Vav3 KO mice revealed a physiological role in sympathetic nervous system control—Vav3 deficiency causes hypertension and tachycardia through catecholamine-driven renin-angiotensin activation.

    Evidence DH domain deletion with PI3K inhibitor and dominant-negative Akt epistasis in prostate cancer cells; Vav3 KO mice with pharmacological blockade of sympathetic/RAS pathways and catecholamine measurements

    PMID:16762975 PMID:16767097

    Open questions at the time
    • Cell type and circuit mediating sympathoexcitation not identified
    • Whether AR coactivation via DH domain is GEF-dependent or -independent not fully reconciled with PH-domain findings
  7. 2009 High

    Transcriptional regulation of VAV3 by AhR was established (ChIP on vav3 promoter), and Vav3 was shown to control vascular smooth muscle proliferation/migration through Src-dependent Rac1-PAK activation, expanding VAV3's role to vascular biology.

    Evidence ChIP of AhR on vav3 promoter, Vav3 KO MEFs, Rac1/ROCK pharmacology; siRNA screen of 27 Rho GEFs, catalytic mutant, Src inhibitor, and dominant-negative Rac1 in smooth muscle cells

    PMID:19158396 PMID:19969623

    Open questions at the time
    • Whether AhR-Vav3 axis operates in all tissues where both are expressed not tested
    • Which Src-family member is the primary VAV3 kinase in smooth muscle not specified
  8. 2010 High

    In vivo studies established VAV3 as an effector of AhR in cardiorespiratory control and demonstrated its requirement for cerebellar Purkinje cell dendritogenesis and granule cell survival/migration.

    Evidence Parallel phenotyping of Ahr−/− and Vav3−/− mice with shared cardiorespiratory and GABAergic phenotypes; Vav3 KO histology, primary neuronal cultures, motor coordination tests

    PMID:20089829 PMID:21115475

    Open questions at the time
    • GTPase substrate for dendritogenesis not identified
    • Whether AhR-Vav3 circuit operates cell-autonomously in neurons unknown
  9. 2011 High

    Nuclear localization of VAV3 was shown to depend on the PH domain, and sequential ChIP proved VAV3 is physically present on AR target gene enhancer chromatin, establishing a direct nuclear coactivator role independent of membrane GEF activity.

    Evidence Sequential ChIP, nuclear/membrane targeting constructs, subcellular fractionation, AR reporter assays

    PMID:21765461

    Open questions at the time
    • Nuclear import mechanism not identified (no NLS mapped)
    • Whether nuclear VAV3 has additional chromatin targets beyond AR not explored
  10. 2012 High

    Four studies expanded VAV3's mechanistic portfolio: VAV3 interacts with AR splice variant AR-V7 promoting its nuclear localization and ligand-independent activity in CRPC; VAV3 is essential for BCR-ABL leukemogenesis via Rac/PAK/apoptosis regulation phenocopying Rac2 loss; Cdc37 co-chaperone potentiates VAV3-AR coactivation independent of GEF activity; and EphA2-VAV3-Rac1 signaling drives metastasis.

    Evidence Co-IP of AR-V7 with Vav3, nuclear fractionation, soft-agar growth; Vav3/Rac2 KO BCR-ABL models with apoptosis readouts; yeast two-hybrid/GST/co-IP for Cdc37-Vav3 with AR N-C interaction assay; EphA2-Vav3 co-IP, Rac1 assay, in vivo metastasis model

    PMID:22659453 PMID:22692505 PMID:23023561 PMID:23281476

    Open questions at the time
    • How Cdc37 enhances VAV3 coactivator function mechanistically not clear
    • Whether EphA2-Vav3 interaction is direct or mediated by intermediate adaptors not resolved
  11. 2016 High

    TRAF6 was identified as a direct DH-domain interactor of VAV3 within the RANK signaling complex, enabling mutual recruitment to RANK and activation of NF-κB/MAPK/NFATc1 for osteoclastogenesis—connecting VAV3 to TNF receptor superfamily signaling.

    Evidence MS-based proteomics, GST pulldown domain mapping, reciprocal co-IP, RANK cytoplasmic tail mutants, downstream signaling assays

    PMID:27507811

    Open questions at the time
    • Whether TRAF6 binding affects VAV3 GEF activity directly not tested
    • Role in non-osteoclast RANK-expressing cells unknown
  12. 2018 High

    Two studies extended VAV3 to endothelial barrier function and myelination: VAV3 activates Rap1 (a new substrate beyond classical Rho GTPases) to maintain high-resistance endothelial barriers, and VAV3 loss in oligodendrocytes accelerates differentiation but impairs myelination through altered RhoA dynamics.

    Evidence Rap1 activation assay with DH mutants, transendothelial resistance, in vivo permeability; Vav3 KO OPC differentiation, synthetic fiber myelination, FRET-based RhoA biosensors

    PMID:29858212 PMID:30450647

    Open questions at the time
    • Whether Rap1 is a direct VAV3 substrate or activated indirectly not fully established
    • Mechanism by which VAV3 coordinately promotes OPC differentiation yet impairs wrapping unknown
  13. 2020 High

    ERBB4 was shown to phosphorylate VAV3's activation domain via specific tyrosines and SH2-domain interaction to drive breast cancer migration, while in CF airway epithelium, apically mislocalized VAV3 drives β1-integrin/fibronectin-dependent Pseudomonas adhesion.

    Evidence MS-based proteomics with ERBB4 tyrosine mutagenesis, VAV3 SH2 mutant, shRNA, migration assays; RNA-seq, apical localization imaging, Vav3 KD, bacterial adhesion assay

    PMID:32561640 PMID:32640241

    Open questions at the time
    • Whether VAV3 GEF activity is required for CF phenotype not tested
    • Downstream GTPase target in CF epithelium not identified
  14. 2021 High

    A VAV3-targeting small molecule (IODVA1) was validated using Vav3-null epistasis, confirming VAV3 as a druggable target: IODVA1 inhibits RAC activation and overcomes TKI resistance in BCR-ABL ALL.

    Evidence Small-molecule binding assay, Vav3 KO cells as negative control, RAC activation assay, murine and patient-derived xenograft models

    PMID:34711926

    Open questions at the time
    • Binding site on VAV3 not structurally defined
    • Off-target effects on other Vav family members not excluded
  15. 2022 High

    Nuclear VAV3 was shown to interact with PRC1 components (Bmi1, Ring1b) and regulate H2AK119 ubiquitination via GEF-dependent nuclear Rac activation, establishing a chromatin-regulatory axis controlling leukemic self-renewal distinct from its cytoplasmic role.

    Evidence Nuclear co-IP of VAV3 with PRC1 components, GEF-dead mutant, ChIP for H2AK119Ub, Bmi1 S314 phosphorylation mutagenesis, Vav3 KO leukemia models

    PMID:35650206

    Open questions at the time
    • Whether nuclear VAV3-PRC1 interaction occurs in non-leukemic cells unknown
    • How nuclear Rac activation connects to Ring1b E3 ligase activity mechanistically not resolved
    • Whether this mechanism extends to other PRC1-regulated loci beyond those studied not explored
  16. 2023 High

    Post-transcriptional regulation of VAV3 was established: HuR binds and stabilizes Vav3 mRNA in CF epithelial cells, and disruption of this interaction reduces VAV3 overexpression and prevents bacterial adhesion.

    Evidence RNA immunoprecipitation of HuR-Vav3 mRNA, HuR interaction disruption, epithelial integrity and bacterial adhesion assays

    PMID:36602863

    Open questions at the time
    • Specific AU-rich element in Vav3 mRNA bound by HuR not mapped
    • Whether HuR-Vav3 mRNA regulation operates in non-CF contexts unknown
  17. 2024 High

    STAT3 was identified as a transcriptional repressor of VAV3 in hepatocytes; VAV3 deficiency impairs GLUT4 vesicle translocation and glucose homeostasis, linking VAV3 to metabolic regulation beyond its known cytoskeletal and nuclear roles.

    Evidence ChIP and reporter assays for STAT3 on VAV3 promoter, VAV3 KO, GLUT4 translocation imaging, glucose uptake assay, AAV8-mediated VAV3 rescue in vivo

    PMID:38617550

    Open questions at the time
    • GTPase substrate mediating GLUT4 vesicle translocation not identified
    • Whether this function is GEF-dependent or -independent not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic-resolution structure of full-length VAV3 in active and inactive states; the mechanism of PH domain-dependent nuclear import; how nuclear GEF-dependent and GEF-independent functions are coordinated; and the identity of VAV3 substrates mediating GLUT4 trafficking and myelination.
  • No atomic-resolution full-length structure available
  • Nuclear import mechanism (NLS or piggyback) not identified
  • Relative contribution of GEF-dependent vs. GEF-independent nuclear functions in different cell types not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0140110 transcription regulator activity 5 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 1
Partners
BMI1CDC37ERBB4RAC1RHOASLP76SYKTRAF6
Complex memberships
NPM-ALK-Src-Vav3 complexRANK-TRAF6-VAV3 signaling complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Vav3 functions as a GDP/GTP nucleotide exchange factor (GEF) for RhoA, RhoG, and to a lesser extent Rac1, physically binding to the nucleotide-free states of those GTPases via its DH and ZF domains; tyrosine phosphorylation stimulates this activity, while deletion of the calponin-homology region renders it constitutively active. In vitro nucleotide exchange assays, co-precipitation with nucleotide-free GTPases, loss-of-function mutations in DH/PH/ZF domains, actin cytoskeleton imaging Molecular and cellular biology High 10523675
1999 Expression of truncated (constitutively active) Vav3 induces stress fibers, lamellipodia, membrane ruffles, and binucleated cells (cytokinesis defects), requiring only the DH-PH-ZF central region but not the C-terminal SH3-SH2-SH3 regions. Transient expression of Vav3 truncation mutants, actin immunofluorescence, multinucleation assay Molecular and cellular biology High 10523675
2000 Vav3 is tyrosine phosphorylated and associates with multiple receptor protein tyrosine kinases (EGFR, Ros, IR, IGFR) and downstream molecules (Shc, Grb2, PLCγ, PI3K) upon ligand stimulation; overexpression activates Rac1 and Cdc42 (and RhoA with N-terminal truncation). Co-immunoprecipitation, GST-fusion GTPase-binding domain pulldown assays, in vitro binding assays Molecular and cellular biology High 11094073
2002 Vav3 cell-cycle expression is regulated: it is transiently up-regulated during mitosis in HeLa cells, and enforced Vav3 expression perturbs cytokinesis, producing multinucleated cells in a RhoA-dependent manner requiring phosphorylation of tyrosine 173. Cell-cycle synchronization, Western blot, enforced expression, dominant-negative RhoA epistasis, Y173 phosphorylation mutants Proceedings of the National Academy of Sciences of the United States of America High 11917103
2002 Vav3 regulates B cell receptor signaling by promoting Rac1-dependent PI3K activation, sustaining PIP3 production; loss of Vav3 reduces PIP3, calcium mobilization, and JNK activation, phenotypes rescued by deletion of the PIP3-phosphatase SHIP. B cell line Vav3 knockout, dominant-negative Rac1 expression, SHIP deletion epistasis, PIP3 measurement The Journal of experimental medicine High 11805146
2002 PI3K and Rho family GTPases (Rac1, RhoA, Cdc42) are differentially required for Vav3-induced focus formation, colony formation, morphological changes, and cell motility; PI3K, Akt, and p70 S6K are required for transformation, whereas cytoskeletal changes are PI3K/MAPK-independent. PI3K/MAPK inhibitors, dominant-negative GTPase mutants, focus/colony formation assays, cell motility assays The Journal of biological chemistry High 11884391
2002 The adaptor protein APS binds the N-terminal calponin-homology (autoinhibitory) domain of Vav3, stabilized by Lck-mediated tyrosine phosphorylation of Vav3; APS binding relieves autoinhibition and enhances Lck-mediated Vav3 phosphorylation, increasing transforming activity. Co-immunoprecipitation, domain-mapping pulldowns, focus formation assays, kinase assays Oncogene High 12400014
2005 Vav3-deficient osteoclasts show defective actin cytoskeleton organization, polarization, spreading, and resorptive activity due to impaired signaling downstream of the M-CSF receptor and αvβ3 integrin; Syk tyrosine kinase is identified as a key upstream regulator of Vav3 in osteoclasts. Vav3 knockout mice, actin staining, bone resorption assays, genetic/biochemical epistasis with Syk Nature medicine High 15711558
2005 Local PIP3 accumulation recruits Vav2 and Vav3 to activate Rac1/Cdc42 at neurite protrusion sites; Vav2/Vav3 are required for the PI3K–Rac1/Cdc42 positive feedback loop driving NGF-induced neurite outgrowth in PC12 cells. FRET-based activity imaging, RNAi knockdown, live-cell imaging of PIP3 and GTPase activity Molecular biology of the cell High 15728722
2005 Vav3 membrane translocation and immunological synapse recruitment during T cell activation require its SH2 domain and SH3-SH2-SH3 regions for SLP-76 binding; TCR-induced Vav3-SLP-76 association is abrogated in Lck-, ZAP-70-, LAT-, and SLP-76-deficient T cells; Vav3 contributes to NFAT activation, with Y173 phosphorylation enhancing (not required for) this function. SH2 point mutation, domain deletions, co-immunoprecipitation, T cell-deficient lines, NFAT reporter assays, confocal microscopy The Journal of biological chemistry High 15708849
2005 Single-particle electron microscopy reveals that inactive (unphosphorylated) Vav3 adopts a closed conformation via interdomain interactions, and tyrosine phosphorylation induces global conformational rearrangements distinct from the constitutively active N-terminally deleted form. Single-particle electron microscopy of unphosphorylated, phosphorylated, and N-terminally truncated Vav3 proteins The EMBO journal High 15775967
2005 Vav3 potentiates androgen receptor (AR) transcriptional activity through a mechanism requiring the pleckstrin homology domain but independent of GEF activity; Vav3 does not directly interact with AR or increase AR protein levels; Vav3 enhances AR activity at sub-nanomolar androgen via AF1. Reporter gene assays, Vav3 knockdown, domain deletion/mutation, co-immunoprecipitation Molecular endocrinology (Baltimore, Md.) High 16384856
2006 Vav3-deficient mice exhibit sympathetic hyperactivity from birth, tachycardia, systemic arterial hypertension, and cardiovascular remodeling, mediated by elevated catecholamines activating the renin-angiotensin system; pharmacological blockade of sympathetic/renin-angiotensin responses confirms causative hierarchy. Vav3 knockout mice, pharmacological epistasis with adrenergic/RAS blockers, catecholamine measurements, cardiovascular phenotyping Nature medicine High 16767097
2006 Vav3 activates AR via the DH domain; overexpression elevates phospho-Akt in prostate cancer cells, and PI3K inhibitors block Vav3-enhanced AR activity; Vav3 promotes androgen-independent growth via PI3K-Akt pathway. DH domain deletion, AR reporter assays, PI3K inhibitors, dominant-negative Akt, Western blot for pAkt Molecular endocrinology (Baltimore, Md.) High 16762975
2007 NPM-ALK activates Rac1 through Vav3 in ALCL cells; Vav3 forms a signaling complex with NPM-ALK, c-Src, and Lyn, associating via its SH2 domain with tyrosine 343 of NPM-ALK; Src kinases control Vav3 phosphorylation by NPM-ALK; Vav3 is required for NPM-ALK-induced cell motility and invasion. Co-immunoprecipitation of endogenous complex, SH2-mutant Vav3, Vav3-specific shRNA, dominant-negative Rac1, Rac1 activation assay Oncogene High 17998938
2008 Vav3 complexes with estrogen receptor α (ERα) and enhances ERα transcriptional activity via a mechanism requiring the DH domain and partly through PI3K-Akt signaling. GST pull-down, co-immunoprecipitation, ERα reporter assays, domain deletions, PI3K inhibitors, siRNA knockdown BMC cancer High 18518979
2009 The aryl hydrocarbon receptor (AhR) transcriptionally regulates constitutive Vav3 expression by binding the vav3 promoter; loss of AhR reduces Vav3-dependent Rac1 activity and increases RhoA/ROCK pathway activity, leading to increased F-actin stress fibers, focal adhesion depolarization, and enhanced cell spreading/adhesion; these defects are phenocopied by Vav3 siRNA knockdown or in Vav3-/- MEFs. ChIP demonstrating AhR recruitment to vav3 promoter, Vav3 siRNA, Vav3-/- MEFs, Rac1 activity assays, pharmacological Rac1 and ROCK inhibitors, actin/adhesion imaging Molecular biology of the cell High 19158396
2009 Vav3 controls vascular smooth muscle cell proliferation and migration through Src tyrosine kinase-dependent activation of Rac1 and its effector PAK; catalytically inactive Vav3 lacks this effect; Rac1 enrichment at membrane is Vav3-dependent. siRNA screen of 27 Rho GEFs, Vav3 overexpression, catalytic mutant, Src inhibitor SU6656, dominant-negative Rac1-N17, PAK activation assay, membrane fractionation Cardiovascular research High 19969623
2010 AhR regulates Vav3 expression in kidney, lung, heart, liver, and brainstem in vivo; AhR-deficient mice display GABAergic transmission defects and cardiorespiratory phenotypes (hypertension, tachypnea, sympathoexcitation) similar to Vav3-/- mice, establishing Vav3 as a downstream effector of AhR in a defined subset of developmental and physiological functions. Ahr-/- and Vav3-/- mouse comparison, RT-PCR/Western blot tissue expression, electrophysiology of ventrolateral medulla The Journal of biological chemistry High 21115475
2010 Vav3 contributes to Purkinje cell dendritogenesis, granule cell survival, and timely granule cell migration in the cerebellum; Vav3-/- mice show postnatal motor coordination deficits; Vav3 is required for dendrite branching but not primary dendritogenesis in primary neuronal cultures. Vav3 knockout mice, histological analysis, primary Purkinje/granule cell cultures, motor coordination tests Molecular biology of the cell High 20089829
2011 Vav3 localizes to both cytoplasm and nucleus; nuclear localization depends on the PH domain; nuclear Vav3 is recruited to AR target gene enhancer chromatin complexes (demonstrated by sequential ChIP); membrane-targeted Vav3 cannot coactivate AR, but nuclear targeting of a PH mutant rescues AR coactivation, establishing a nuclear GEF-independent function for Vav3 in AR regulation. Sequential chromatin immunoprecipitation (ChIP), membrane/nuclear targeting constructs, subcellular fractionation, AR reporter assays Oncogene High 21765461
2012 Vav3 physically interacts with the AR splice variant AR3 (AR-V7); Vav3 promotes nuclear localization of AR3; Vav3 potently enhances ligand-independent transcriptional activity of AR3 and ARv567es, and is required for proliferation and anchorage-independent growth in CRPC cells. Co-immunoprecipitation of AR3-Vav3, nuclear fractionation, Vav3 knockdown, AR reporter assays, soft-agar growth Molecular endocrinology (Baltimore, Md.) High 23023561
2012 Vav3 is required for BCR-ABL-driven B-cell lymphoblastic leukemogenesis; Vav3 deficiency induces apoptosis of leukemic progenitors, decreases Rho GTPase and PAK activation, and increases pro-apoptotic Bad phosphorylation/Bax/Bak/Bik; Vav3 deficiency phenocopies Rac2 deficiency. Vav3 KO mouse model of BCR-ABL leukemia, epistasis with Rac2-/-, apoptosis assays, GTPase activation assays Blood High 22692505
2012 Co-chaperone Cdc37 interacts with Vav3 (identified by yeast two-hybrid, confirmed by GST pulldown and co-IP); Cdc37 potentiates Vav3 coactivation of AR and enhances AR N-C interaction without affecting Vav3 GEF activity or localization; disruption of Vav3-Cdc37 interaction inhibits AR activity and prostate cancer proliferation. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, AR reporter assays, AR N-C interaction assay, cell proliferation assays The Journal of biological chemistry High 23281476
2012 Stimulation of EphA2 by ephrinA1 leads to recruitment and tyrosine phosphorylation of Vav3, activating Rac1 and increasing migration and invasion; Vav3 reduction decreases lymph node and bone metastasis in vivo. Co-immunoprecipitation of EphA2-Vav3, Rac1 activation assay, Vav3 siRNA, in vivo metastasis model Cancer research High 22659453
2014 Phosphorylation of 3BP2 Tyr426 by Syk is required for the inducible interaction between 3BP2 and the SH2 domain of Vav3; this interaction is required for BCR-induced Rac1 activation downstream of Vav3. Site-directed mutagenesis of 3BP2 tyrosines, co-immunoprecipitation of 3BP2-Vav3 SH2, Rac1 activation assay in DT40 cells Experimental cell research High 24406398
2016 TRAF6 directly interacts with Vav3 via its coiled-coil domain binding to the DH domain of Vav3 within the RANK signaling complex, independent of TRAF6 ubiquitination; this TRAF6-Vav3 interaction enables mutual recruitment to RANK and enhances NF-κB, MAPK, and NFATc1 activation to promote osteoclastogenesis. Proteomics/MS identification of TRAF6 interactors, GST pulldown domain mapping, co-immunoprecipitation, RANK cytoplasmic tail mutants, downstream signaling assays The Journal of biological chemistry High 27507811
2018 Vav3 is exclusively expressed in microvascular endothelial cells and its DH domain-dependent activation of Rap1 is required for cortical actin rearrangement and high-resistance endothelial barrier function; Vav3 inactivation in vivo increases vascular leakage. Endothelial gene expression correlation, Vav3 ectopic expression, DH domain mutants, Rap1 activation assay, transendothelial resistance measurements, in vivo vascular permeability assay The Journal of cell biology High 29858212
2018 Vav3 loss in oligodendrocytes accelerates OPC differentiation but impairs myelination of synthetic microfibers and remyelination in cerebellar slice cultures; Vav3-deficient oligodendrocytes show altered RhoA GTPase activation profiles measured by FRET biosensors. Vav3 KO mice, OPC differentiation assay, myelination assay on synthetic fibers, lysolecithin/cuprizone demyelination models, FRET-based RhoA biosensors Glia High 30450647
2020 ERBB4 interacts with VAV3 via kinase activity and specific tyrosines (Tyr-1022, Tyr-1162) of ERBB4 and the VAV3 SH2 domain; ERBB4 stimulates tyrosine phosphorylation of the VAV3 activation domain, and VAV3 GEF activity is required for ERBB4-stimulated breast cancer cell migration. MS-based proteomics, targeted MS, co-immunoprecipitation, site-directed mutagenesis of ERBB4/VAV3, dominant-negative VAV3, shRNA knockdown, migration assays The Journal of biological chemistry High 32561640
2020 Vav3 is apically overexpressed in cystic fibrosis (CF) airway epithelial cells, associates with active β1 integrin luminally, and increases luminal fibronectin deposition; Vav3 inhibition normalizes fibronectin/β1-integrin expression and prevents Pseudomonas aeruginosa adhesion to the CF epithelium. RNA-seq, immunofluorescence/apical localization imaging, Vav3 knockdown, fibronectin deposition assay, bacterial adhesion assay Cell reports High 32640241
2021 The small molecule IODVA1 binds VAV3 to inhibit RAC activation and signaling in BCR-ABL1-driven ALL; leukemic cells from Vav3-null mice do not respond to IODVA1, confirming VAV3 as the target; IODVA1 overcomes TKI resistance by durably suppressing RAC signaling. Small-molecule binding assay, Vav3 KO epistasis, RAC activation assay, murine and patient-derived xenograft models Leukemia High 34711926
2022 In BCR-ABL+ B-ALL, Vav3 becomes predominantly nuclear and interacts with BCR-ABL, Rac, and PRC1 proteins Bmi1, Ring1b, and Ezh2; Vav3 GEF activity is required for nuclear Rac activation, Bmi1-dependent self-renewal, H2AK119 mono-ubiquitination, and PRC1 target gene repression; Vav3 prevents Phlpp2/Akt(S473)-dependent phosphorylation of Bmi1-S314. Co-immunoprecipitation of nuclear Vav3 with PRC1 components, GEF-dead mutant, nuclear fractionation, ChIP for H2AK119Ub, Bmi1 phosphorylation/mutagenesis, Vav3 KO leukemia models Nature communications High 35650206
2023 HuR mRNA-stabilizing protein accumulates in the cytoplasm of CF airway epithelial cells, binds Vav3 mRNA, and stabilizes it; disruption of the HuR-Vav3 mRNA interaction reduces Vav3 overexpression, restores epithelial integrity, and prevents Pseudomonas aeruginosa adhesion. RNA immunoprecipitation (RIP) of HuR-Vav3 mRNA, HuR-Vav3 interaction disruption, epithelial integrity assays, bacterial adhesion assay JCI insight High 36602863
2024 STAT3 acts as a transcriptional repressor of VAV3 in hepatocytes during high-fat diet-induced MAFLD; VAV3 deficiency impairs GLUT4 vesicle membrane translocation and glucose homeostasis, and promotes intracellular cholesterol accumulation; AAV8-mediated VAV3 restoration improves glucose homeostasis and attenuates hepatic cholesterol accumulation in vivo. ChIP/reporter for STAT3 on VAV3 promoter, VAV3 KO, GLUT4 translocation imaging, glucose uptake assay, AAV rescue in vivo International journal of biological sciences High 38617550
2017 DNMT3B overexpression methylates the VAV3 gene promoter, leading to transcriptional downregulation of VAV3; this identifies VAV3 as an epigenetic target of de novo DNA methyltransferase DNMT3B. DNMT3B overexpression in HaCaT cells, methylation-specific analysis of VAV3 promoter, gene expression microarray and RT-PCR American journal of cancer research Medium 28123849
2004 Vav1 and Vav3 play critical but redundant roles in PLCγ2 activation downstream of the ITAM-coupled collagen receptor GPVI in platelets; Vav3 is tyrosine-phosphorylated upon GPVI activation; Vav1/3 double-deficient platelets show markedly reduced aggregation and PLCγ2 phosphorylation. Vav single and double knockout mice, GPVI stimulation, PLCγ2 phosphorylation assay, platelet aggregation assay The Journal of biological chemistry High 15456756
2017 The atypical C1 domain of Vav3 lacks phorbol ester/diacylglycerol binding due to specific residues; engineering phorbol ester binding into the Vav3 C1 domain disrupts GEF activity and shifts Vav3 localization to the membrane, altering its protein interaction profile. C1 domain mutagenesis, phorbol ester binding assay, GEF activity assay, membrane localization imaging Cellular signalling Medium 28927664
2025 SYK phosphorylates Vav3 in osteoclasts; SYK and Vav3 colocalize at the leading edge; SYK knockdown reduces Vav3 phosphorylation and actin ring formation, impairing osteoclast bone resorption. SYK shRNA knockdown, Western blot for pVav3/pSYK, colocalization imaging (phalloidin/WGA staining), bone resorption lacunae assay Cell biology international Medium 40787875

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins. Molecular and cellular biology 237 10523675
2005 Vav3 regulates osteoclast function and bone mass. Nature medicine 226 15711558
2008 The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. The American journal of pathology 152 19008376
2000 Vav3 mediates receptor protein tyrosine kinase signaling, regulates GTPase activity, modulates cell morphology, and induces cell transformation. Molecular and cellular biology 126 11094073
2005 Local phosphatidylinositol 3,4,5-trisphosphate accumulation recruits Vav2 and Vav3 to activate Rac1/Cdc42 and initiate neurite outgrowth in nerve growth factor-stimulated PC12 cells. Molecular biology of the cell 124 15728722
2002 Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation. The Journal of experimental medicine 115 11805146
2012 The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. Science signaling 96 23033540
2020 Up-regulated LINC01234 promotes non-small-cell lung cancer cell metastasis by activating VAV3 and repressing BTG2 expression. Journal of hematology & oncology 91 31959200
2006 Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. Nature medicine 89 16767097
2016 Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling. International immunopharmacology 83 27930970
2004 Vav1 and vav3 have critical but redundant roles in mediating platelet activation by collagen. The Journal of biological chemistry 79 15456756
2002 Distinct role of phosphatidylinositol 3-kinase and Rho family GTPases in Vav3-induced cell transformation, cell motility, and morphological changes. The Journal of biological chemistry 69 11884391
2009 The dioxin receptor regulates the constitutive expression of the vav3 proto-oncogene and modulates cell shape and adhesion. Molecular biology of the cell 67 19158396
2006 Vav3 oncogene is overexpressed and regulates cell growth and androgen receptor activity in human prostate cancer. Molecular endocrinology (Baltimore, Md.) 67 16762975
2020 Exosomal miR-499a-5p Inhibits Endometrial Cancer Growth and Metastasis via Targeting VAV3. Cancer management and research 60 33408524
2008 Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer. BMC cancer 60 18518979
2012 Vav3-rac1 signaling regulates prostate cancer metastasis with elevated Vav3 expression correlating with prostate cancer progression and posttreatment recurrence. Cancer research 59 22659453
2005 Vav3, a Rho GTPase guanine nucleotide exchange factor, increases during progression to androgen independence in prostate cancer cells and potentiates androgen receptor transcriptional activity. Molecular endocrinology (Baltimore, Md.) 58 16384856
2010 Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene. The Journal of biological chemistry 54 21115475
2007 Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas. Oncogene 49 17998938
2012 Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival. Molecular endocrinology (Baltimore, Md.) 48 23023561
2010 VAV2 and VAV3 as candidate disease genes for spontaneous glaucoma in mice and humans. PloS one 48 20140222
2016 Overexpression of miR-499-5p inhibits non-small cell lung cancer proliferation and metastasis by targeting VAV3. Scientific reports 44 26972445
2011 A novel nuclear role for the Vav3 nucleotide exchange factor in androgen receptor coactivation in prostate cancer. Oncogene 44 21765461
2019 Circular RNA Vav3 sponges gga-miR-375 to promote epithelial-mesenchymal transition. RNA biology 39 30608205
2010 Vav3-deficient mice exhibit a transient delay in cerebellar development. Molecular biology of the cell 39 20089829
2012 Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation, and survival. Blood 38 22692505
2005 Global conformational rearrangements during the activation of the GDP/GTP exchange factor Vav3. The EMBO journal 37 15775967
2010 The molecular mechanism of Vav3 oncogene on upregulation of androgen receptor activity in prostate cancer cells. International journal of oncology 36 20126983
2002 Vav3 is regulated during the cell cycle and effects cell division. Proceedings of the National Academy of Sciences of the United States of America 36 11917103
2000 Major transcript variants of VAV3, a new member of the VAV family of guanine nucleotide exchange factors. Gene 36 10713454
2008 Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. Cancer research 35 18676865
2005 Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76. The Journal of biological chemistry 35 15708849
2010 Variations in NTF4, VAV2, and VAV3 genes are not involved with primary open-angle and primary angle-closure glaucomas in an indian population. Investigative ophthalmology & visual science 34 20463313
2014 VAV3 mediates resistance to breast cancer endocrine therapy. Breast cancer research : BCR 31 24886537
2010 Nonobese diabetic congenic strain analysis of autoimmune diabetes reveals genetic complexity of the Idd18 locus and identifies Vav3 as a candidate gene. Journal of immunology (Baltimore, Md. : 1950) 29 20363978
2009 The Rho protein exchange factor Vav3 regulates vascular smooth muscle cell proliferation and migration. Cardiovascular research 29 19969623
2018 Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers. The Journal of cell biology 28 29858212
2020 LINC00265 targets miR-382-5p to regulate SAT1, VAV3 and angiogenesis in osteosarcoma. Aging 25 33109774
2018 The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions. Glia 25 30450647
2017 DNMT3B modulates the expression of cancer-related genes and downregulates the expression of the gene VAV3 via methylation. American journal of cancer research 24 28123849
2013 Inhibition of gastric cancer cell growth and invasion through siRNA-mediated knockdown of guanine nucleotide exchange factor Vav3. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 24 24072493
2013 Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia. Molecular cancer 23 23566222
2012 Clinical significance of increased guanine nucleotide exchange factor Vav3 expression in human gastric cancer. Molecular cancer research : MCR 23 22544459
2010 A remarkable new target gene for the dioxin receptor: The Vav3 proto-oncogene links AhR to adhesion and migration. Cell adhesion & migration 23 20190565
2017 Involvement of the guanine nucleotide exchange factor Vav3 in central nervous system development and plasticity. Biological chemistry 22 28214347
2002 Adaptor protein APS binds the NH2-terminal autoinhibitory domain of guanine nucleotide exchange factor Vav3 and augments its activity. Oncogene 22 12400014
2020 Vav3 Mediates Pseudomonas aeruginosa Adhesion to the Cystic Fibrosis Airway Epithelium. Cell reports 21 32640241
2016 Detection of OSR2, VAV3, and PPFIA3 Methylation in the Serum of Patients with Gastric Cancer. Disease markers 21 27143812
2012 Novel interaction between the co-chaperone Cdc37 and Rho GTPase exchange factor Vav3 promotes androgen receptor activity and prostate cancer growth. The Journal of biological chemistry 19 23281476
2021 miR-155-5p predictive role to decelerate foam cell atherosclerosis through CD36, VAV3, and SOCS1 pathway. Non-coding RNA research 16 33869908
2014 The guanine nucleotide exchange factor Vav3 regulates differentiation of progenitor cells in the developing mouse retina. Cell and tissue research 16 25501893
2012 Analysis of the VAV3 as candidate gene for schizophrenia: evidences from voxel-based morphometry and mutation screening. Schizophrenia bulletin 16 22416266
2016 Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis. The Journal of biological chemistry 15 27507811
2014 Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway. Cancer gene therapy 15 25430880
2023 Serum exosome-derived miR-146a-3p promotes macrophage M2 polarization in allergic rhinitis by targeting VAV3 via PI3K/AKT/mTOR pathway. International immunopharmacology 14 37783052
2020 The guanine nucleotide exchange factor VAV3 participates in ERBB4-mediated cancer cell migration. The Journal of biological chemistry 14 32561640
2011 Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer. Oncology reports 14 21455584
2020 HDAC1 promotes artery injury through activation of VAV3 by binding to miR-182-5p in atherosclerotic mice model. Cellular signalling 12 33221374
2013 The Vav3 oncogene enhances the malignant potential of prostate cancer cells under chronic hypoxia. Urologic oncology 12 23403204
2024 The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD. International journal of biological sciences 11 38617550
2023 Targeting HuR-Vav3 mRNA interaction prevents Pseudomonas aeruginosa adhesion to the cystic fibrosis airway epithelium. JCI insight 10 36602863
2022 Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis. Nature communications 10 35650206
2021 Inhibition of the RacGEF VAV3 by the small molecule IODVA1 impedes RAC signaling and overcomes resistance to tyrosine kinase inhibition in acute lymphoblastic leukemia. Leukemia 10 34711926
2015 Inhibition of Vav3 gene can promote apoptosis of human gastric cancer cell line MGC803 by regulating ERK pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 26695150
2014 Tyrosine phosphorylation of 3BP2 is indispensable for the interaction with VAV3 in chicken DT40 cells. Experimental cell research 10 24406398
2024 DDX5 promotes esophageal squamous cell carcinoma growth through sustaining VAV3 mRNA stability. Oncogene 9 39289531
2023 VAV3 regulates glioblastoma cell proliferation, migration, invasion and cancer stem‑like cell self‑renewal. Molecular medicine reports 9 36960857
2014 Vav3, a GEF for RhoA, Plays a Critical Role under High Glucose Conditions. Endocrinology and metabolism (Seoul, Korea) 9 25309796
2023 VAV3 in human cancers: Mechanism and clinical implication. Pathology, research and practice 8 37467637
2020 Deletion of the Nucleotide Exchange Factor Vav3 Enhances Axonal Complexity and Synapse Formation but Tampers Activity of Hippocampal Neuronal Networks In Vitro. International journal of molecular sciences 8 32013053
2013 Molecular genetic analysis of primary open-angle glaucoma, normal tension glaucoma, and developmental glaucoma for the VAV2 and VAV3 gene variants in Japanese subjects. Biochemical and biophysical research communications 7 23402756
2023 The role of Vav3 expression for inflammation and cell death during experimental myocardial infarction. Clinics (Sao Paulo, Brazil) 5 37591108
2022 The Rho guanosine nucleotide exchange factors Vav2 and Vav3 modulate epidermal stem cell function. Oncogene 5 35534539
2020 VAV3 rs7528153 and VAV3-AS1 rs1185222 polymorphisms are associated with an increased risk of developing hypertension. European journal of internal medicine 5 32540412
2017 A Novel Vav3 Homolog Identified in Lamprey, Lampetra japonica, with Roles in Lipopolysaccharide-Mediated Immune Response. International journal of molecular sciences 5 28937614
2018 (Iso-)form Matters: Differential Implication of Vav3 Variants in Ovarian Cancer. The oncologist 4 29674438
2017 The clinical value of Vav3 in peripheral blood for predicting lymphatic metastasis of gastric cancer. British journal of biomedical science 4 28513273
2016 VAV3 Gene Polymorphism Is Associated with Paget's Disease of Bone. Genetic testing and molecular biomarkers 4 27172236
2022 Vav3-Deficient Astrocytes Enhance the Dendritic Development of Hippocampal Neurons in an Indirect Co-culture System. Frontiers in cellular neuroscience 3 35237130
2017 The C1 domain of Vav3, a novel potential therapeutic target. Cellular signalling 3 28927664
2016 [Association between polymorphism in Vav3 genes and risk of primary prostatic cancer in Chinese Han population]. Zhonghua bing li xue za zhi = Chinese journal of pathology 3 27430689
2025 Circular RNA Vav3 mediated ALV-J inhibition of autophagy by modulating the gga-miR-375/CIP2A axis and activating AKT. Poultry science 2 39987600
2022 The guanine nucleotide exchange factor Vav3 intervenes in the migration pathway of oligodendrocyte precursor cells on tenascin-C. Frontiers in cell and developmental biology 2 36531963
2021 The effect of VAV3 polymorphisms on thyroid cancer. Endocrine 2 34292486
2025 Unravelling the roles of Vav3 in cytoskeletal control and angiogenesis. Life sciences 1 40618919
2022 Rs7537605 polymorphism in VAV3 gene and rs28665122 polymorphism in SEPS gene are not associated with Hashimoto's thyroiditis in North-East Algerian population. African health sciences 1 37092056
2015 [Effect and mechanism of Vav3 on the proliferation of human gastric cancer SGC7901 cells]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 1 25975784
2026 Gut microbiota-derived trimethylamine-N-oxide protects pulmonary vascular barrier integrity via Vav guanine nucleotide exchange factor 3 (VAV3)-mediated cytoskeletal remodelling in acute lung injury. British journal of pharmacology 0 42025389
2025 Spleen Tyrosine Kinase Exacerbates Anti-Citrullinated Protein/Peptide Antibody-Mediated Osteoclast Bone Resorption via Promotion of Vav3 Phosphorylation. Cell biology international 0 40787875
2025 Bcl11a deficiency in cerebellar Purkinje cells causes ataxia and autistic-like behavior by altering Vav3. Molecular psychiatry 0 40855003