| 1999 |
Vav3 functions as a GDP-GTP nucleotide exchange factor for RhoA, RhoG, and (to a lesser extent) Rac1; it binds physically to the nucleotide-free states of these GTPases. This activity is stimulated by tyrosine phosphorylation and becomes constitutively active upon deletion of the calponin-homology (CH) region. The DH and ZF domains are both essential for GTPase binding and activation, with the ZF region working coordinately with the catalytic DH region. |
Nucleotide exchange assays, physical binding assays, deletion/loss-of-function mutagenesis, actin cytoskeleton readouts in transfected cells |
Molecular and cellular biology |
High |
10523675
|
| 1999 |
Expression of activated (N-terminally truncated) Vav3 induces actin relocalization, stress fibers, lamellipodia, membrane ruffles, and cytokinesis defects (binucleated cells), requiring only the DH-PH-ZF central region and not the C-terminal SH3-SH2-SH3 domains. |
Truncation mutant overexpression, fluorescence microscopy of actin cytoskeleton, cytokinesis assay in transfected cells |
Molecular and cellular biology |
High |
10523675
|
| 2000 |
Vav3 interacts with and is tyrosine-phosphorylated downstream of multiple receptor protein tyrosine kinases (EGFR, Ros, insulin receptor, IGF-IR); it also associates with downstream signaling molecules Shc, Grb2, PLC-γ, and PI3K. Overexpression activates Rac1 and Cdc42, while N-terminal truncation (removing CH and acidic domains) activates RhoA and Rac1 but loses Cdc42 activation. |
Yeast two-hybrid, co-immunoprecipitation, in vitro GST-fusion binding assays for active GTPases, transfection in 293T and NIH 3T3 cells |
Molecular and cellular biology |
High |
11094073
|
| 2002 |
Vav3 expression is cell-cycle regulated, being transiently up-regulated during mitosis in HeLa cells. Enforced Vav3 expression perturbs cytokinesis and produces multinucleated cells in a RhoA-dependent manner requiring phosphorylation of the regulatory tyrosine Y173. |
Cell cycle synchronization, Western blot, enforced expression, RhoA dependence assay, dominant-negative and phosphorylation-site mutant analysis |
Proceedings of the National Academy of Sciences |
High |
11917103
|
| 2002 |
Vav3-induced cell transformation (focus formation) requires PI3K/Akt signaling, Rac1, RhoA, and Cdc42, but PI3K/MAPK inhibition does not affect cytoskeletal (lamellipodia/filopodia) changes. Cell motility enhancement depends on PI3K, Rac1, and Cdc42 but not RhoA. |
Focus-formation assays, pharmacological inhibition of PI3K/MAPK, dominant-negative GTPase constructs, cell motility assays in NIH 3T3 cells |
The Journal of biological chemistry |
High |
11884391
|
| 2002 |
The adaptor protein APS binds the N-terminal CH (autoinhibitory) domain of Vav3. This interaction is stabilized by Lck-mediated tyrosine phosphorylation of Vav3, and APS in turn enhances Lck-mediated Vav3 phosphorylation. APS binding to the PH domain of APS–Vav3 CH domain interaction relieves autoinhibition and increases Vav3 transforming activity. |
Co-immunoprecipitation, GST pulldown, focus-formation assays, domain mutant analysis |
Oncogene |
Medium |
12400014
|
| 2002 |
In B cells, Vav3 promotes sustained PIP3 production via Rac1 activation of PI3K, downstream of BCR engagement. Loss of Vav3 attenuates PIP3 generation, calcium mobilization, and JNK activation; these defects are rescued by deletion of the PIP3 phosphatase SHIP. |
B cell line Vav3 knockout, dominant-negative Rac1 expression, PI3K activity assay, PIP3 measurement, SHIP deletion rescue |
The Journal of experimental medicine |
High |
11805146
|
| 2004 |
Vav1 and Vav3 have redundant roles in activating PLCγ2 downstream of the ITAM-coupled collagen receptor GPVI in platelets. Single Vav3 knockout shows normal GPVI response; Vav1/Vav3 double knockout markedly inhibits aggregation, spreading, and PLCγ2 tyrosine phosphorylation upon GPVI stimulation. |
Single and double gene knockout in mice, platelet aggregation assay, spreading assay, Western blot for PLCγ2 phosphorylation |
The Journal of biological chemistry |
High |
15456756
|
| 2005 |
Vav3 is essential for stimulated osteoclast activation in vivo: Vav3-deficient osteoclasts display defective actin cytoskeleton organization, polarization, spreading, and bone resorption due to impaired signaling downstream of M-CSF receptor and αvβ3 integrin. Genetic and biochemical evidence places Syk tyrosine kinase as a crucial upstream regulator of Vav3 in osteoclasts. |
Vav3 knockout mice, bone density measurement, osteoclast functional assays, Syk genetic and biochemical epistasis, co-immunoprecipitation |
Nature medicine |
High |
15711558
|
| 2005 |
During NGF-stimulated neurite outgrowth in PC12 cells, local PIP3 accumulation recruits Vav2 and Vav3 to activate Rac1 and Cdc42. Vav2/Vav3 are required for a positive feedback loop between PI3K and Rac1/Cdc42 that drives localized protrusions; RNAi depletion of Vav2 and Vav3 significantly inhibits Rac1/Cdc42 activation and neurite formation. |
FRET biosensors, RNAi knockdown, live-cell imaging of PIP3 and GTPase activity in PC12 cells |
Molecular biology of the cell |
High |
15728722
|
| 2005 |
TCR-induced membrane translocation and immunological synapse (IS) recruitment of Vav3 requires its SH2 domain-mediated association with SLP-76. Vav3 mutants with disabled SH2 (R697L) or lacking SH3-SH2-SH3 domains fail to bind SLP-76 and do not translocate. Membrane localization depends on upstream signaling via Lck, ZAP-70, LAT, and SLP-76. Vav3 is required for NFAT activation in T cells lacking Vav1. |
Subcellular localization imaging (membrane/IS), Vav3 mutant expression, co-immunoprecipitation with SLP-76, signaling-deficient cell lines (Lck−/−, ZAP-70−/−, LAT−/−, SLP-76−/−), NFAT reporter assay, Vav3 knockdown in Vav1-deficient T cells |
The Journal of biological chemistry |
High |
15708849
|
| 2005 |
Single-particle electron microscopy resolved the structures of inactive (unphosphorylated), active (tyrosine-phosphorylated), and constitutively active (N-terminally deleted) Vav3. Tyrosine phosphorylation induces global conformational rearrangements; the phosphorylated and N-terminally deleted forms have distinct conformations, indicating that constitutive oncogenic activity is structurally more complex than simple relief of autoinhibition. |
Single-particle electron microscopy, structural comparison of three functional states |
The EMBO journal |
High |
15775967
|
| 2005 |
Vav3 potentiates androgen receptor (AR) transcriptional activity in a GEF-independent but pleckstrin homology (PH) domain-dependent manner. Vav3 does not directly interact with AR and does not increase AR protein levels; enhancement of AR activity requires the AR N-terminal activation function 1 (AF1). |
Reporter gene assays, Vav3 knockdown, domain deletion mutants, co-immunoprecipitation (negative result for direct AR interaction) |
Molecular endocrinology |
Medium |
16384856
|
| 2006 |
Vav3 deficiency in mice causes tachycardia, systemic hypertension, and cardiovascular remodeling via sympathetic neuron hyperactivity from birth, leading to elevated catecholamines, renin-angiotensin system activation, and progressive loss of cardiovascular homeostasis. Pharmacological studies confirmed the causative hierarchy of sympathetic → renin-angiotensin events. |
Vav3 knockout mice, blood pressure and heart rate measurement, catecholamine assays, pharmacological blockade of sympathetic and renin-angiotensin systems |
Nature medicine |
High |
16767097
|
| 2006 |
Vav3 is overexpressed in androgen-independent prostate cancer; its DH domain is responsible for AR activation. Vav3 overexpression activates AR via the PI3K-Akt pathway; PI3K inhibitors or dominant-negative Akt attenuate this effect, and PI3K co-transfection enhances it. |
siRNA knockdown, overexpression, AR luciferase reporter assay, PI3K inhibition, dominant-negative Akt, Western blot for pAkt |
Molecular endocrinology |
Medium |
16762975
|
| 2007 |
In NPM-ALK+ anaplastic large cell lymphoma, Vav3 is activated by NPM-ALK and mediates Rac1 activation downstream. Vav3 associates with NPM-ALK via its SH2 domain binding to phospho-Y343 of NPM-ALK, forming a complex with pp60c-src and Lyn. Src kinases control Vav3/Rac1 stimulation. Vav3-specific shRNA and dominant-negative Rac1 inhibit NPM-ALK-induced cell motility and invasion. |
Co-immunoprecipitation, domain mutant analysis (SH2-disabled), shRNA knockdown, dominant-negative Rac1, motility/invasion assays, phospho-Vav3 in patient biopsies |
Oncogene |
High |
17998938
|
| 2008 |
Vav3 complexes physically with ERα (demonstrated by GST pulldown). The DH domain of Vav3 is essential for ERα activation. Vav3 activates ERα partly via the PI3K-Akt pathway and stimulates breast cancer cell growth. |
GST pulldown, luciferase reporter assay, siRNA knockdown, PI3K inhibition, domain deletion analysis |
BMC cancer |
Medium |
18518979
|
| 2009 |
AhR directly regulates constitutive Vav3 mRNA expression in a ligand-independent manner by binding to the vav3 promoter. In AhR-null fibroblasts, reduced Vav3 expression leads to decreased Rac1 activity, increased RhoA/ROCK pathway activation, enlarged cell area with increased F-actin stress fibers, depolarized focal adhesions, and enhanced spreading/adhesion. Re-expression of AhR or Vav3 restores wild-type morphology. |
ChIP of AhR at vav3 promoter, AhR-/- and Vav3-/- MEFs, pharmacological Rac1/ROCK inhibition, siRNA knockdown of Vav3, GTPase activity assays, cell morphology and adhesion assays |
Molecular biology of the cell |
High |
19158396
|
| 2010 |
Aryl hydrocarbon receptor (Ahr) controls Vav3 expression in kidney, lung, heart, liver, and brainstem in a ligand-independent manner. Ahr-/- and Vav3-/- mice share phenotypes of hypertension, tachypnea, and sympathoexcitation, with Ahr-/- mice also showing GABAergic transmission defects in the ventrolateral medulla present in Vav3-/- mice. |
Ahr-/- and Vav3-/- mouse phenotypic comparison, tissue Vav3 expression analysis, Ahr ligand treatment, cardiorespiratory and autonomic measurements |
The Journal of biological chemistry |
High |
21115475
|
| 2011 |
Vav3 localizes to both cytoplasm and nucleus; nuclear localization depends on the PH domain. Membrane targeting of Vav3 abolishes its potentiation of AR activity, while nuclear targeting of a PH mutant rescues AR coactivation. Sequential ChIP shows Vav3 and AR are co-recruited to the same AR target gene enhancer complexes. Vav3 strongly stimulates AR N-terminal–C-terminal (N-C) interaction required for maximal AR transcriptional activity. |
Subcellular fractionation, fluorescence localization, membrane/nuclear targeting constructs, sequential ChIP (re-ChIP), N-C interaction assay, luciferase reporter assay |
Oncogene |
High |
21765461
|
| 2012 |
Vav3 physically interacts with AR splice variant AR3 (AR-V7) as shown by co-immunoprecipitation. Vav3 potently enhances transcriptional activity of AR3 and ARv567es, and promotes nuclear accumulation of AR3. Vav3 or AR3 knockdown greatly reduces CRPC cell proliferation and ligand-independent AR activity. |
Co-immunoprecipitation, nuclear/total AR3 fractionation, siRNA knockdown, luciferase reporter assay, soft agar colony formation |
Molecular endocrinology |
High |
23023561
|
| 2012 |
Vav3 deficiency delays p190-BCR-ABL-driven B-cell lymphoblastic leukemogenesis and phenocopies Rac2 deficiency (a downstream effector), establishing Rac2 as a downstream effector of Vav3 in this context. Vav3 deficiency induces apoptosis of leukemic progenitors with decreased RhoGTPase/PAK activation, increased Bad phosphorylation, and upregulation of Bax, Bak, and Bik. Vav3 activity is only partly ABL TK-dependent, and Vav3 deficiency collaborates with TKIs to inhibit CrkL activation. |
Vav3 knockout and Vav1/Vav2-deficient mouse models, BCR-ABL leukemogenesis assay, apoptosis assays, GTPase activation assays, TKI combination studies in vitro and in vivo |
Blood |
High |
22692505
|
| 2012 |
EphA2 stimulation by ephrinA1 recruits and tyrosine-phosphorylates Vav3, leading to Rac1 activation and increased prostate cancer cell migration and invasion. Reduction of Vav3 decreases para-aortic lymph node and bone metastasis in vivo. |
Receptor stimulation, co-immunoprecipitation, Rac1 activity assay, Vav3 knockdown, in vivo metastasis model |
Cancer research |
Medium |
22659453
|
| 2012 |
Co-chaperone Cdc37 was identified as a Vav3-interacting protein by yeast two-hybrid and confirmed by GST pulldown and co-immunoprecipitation. Cdc37 potentiates Vav3 co-activation of AR transcriptional activity and enhances AR N-C interaction. Disruption of Vav3-Cdc37 interaction inhibits Vav3 enhancement of AR activity and reduces prostate cancer cell proliferation in Vav3-expressing cells. Cdc37 does not affect Vav3 nucleotide exchange activity, protein levels, or subcellular localization. |
Yeast two-hybrid, GST pulldown, co-immunoprecipitation, AR reporter assay, AR N-C interaction assay, cell proliferation assay |
The Journal of biological chemistry |
Medium |
23281476
|
| 2014 |
VAV3 depletion comparatively reduces viability of endocrine-therapy-resistant breast cancer cell models. VAV3 expression is selectively reduced upon ERα depletion or by the compound YC-1, placing VAV3 downstream of ERα in endocrine-resistant breast cancer signaling. |
shRNA-mediated VAV3 depletion, ERα depletion, viability assays, gene expression analysis |
Breast cancer research |
Medium |
24886537
|
| 2016 |
TRAF6's coiled-coil domain directly interacts with the DH domain of Vav3, forming a complex within the RANK signaling complex independent of the TRAF6 ubiquitination pathway. This TRAF6-Vav3 interaction results from cross-talk between TRAF6-binding sites (T6BSs) and the IVVY motif in the RANK cytoplasmic tail, and enhances downstream NF-κB, MAPK, and NFATc1 activation, thereby inducing osteoclastogenesis. |
Proteomic screen for TRAF6-interacting proteins, co-immunoprecipitation, domain-specific interaction mapping, RANK cytoplasmic tail mutants, NF-κB/MAPK/NFATc1 signaling assays |
The Journal of biological chemistry |
High |
27507811
|
| 2017 |
DNMT3B overexpression in HaCaT cells downregulates VAV3 expression via promoter methylation of the VAV3 gene, establishing DNMT3B as a methyltransferase writer that epigenetically represses VAV3. |
DNMT3B overexpression, gene expression microarray, promoter methylation analysis |
American journal of cancer research |
Medium |
28123849
|
| 2017 |
The atypical C1 domain of Vav3 lacks phorbol ester/diacylglycerol binding (analogous to Vav1) due to specific residues. Engineering phorbol ester binding into the modified Vav3 C1 domain disrupts its guanyl nucleotide exchange activity and causes membrane localization upon phorbol ester treatment, accompanied by altered interactions with other signaling proteins. |
Mutagenesis of C1 domain, phorbol ester binding assay, GEF activity assay, subcellular localization analysis, co-immunoprecipitation of signaling partners |
Cellular signalling |
Medium |
28927664
|
| 2018 |
Vav3 is exclusively expressed in microvascular endothelial cells and is associated with a high-resistance barrier phenotype. The barrier-enhancing effect of Vav3 requires its DH domain and downstream activation of Rap1. Vav3 inactivation in vivo increases vascular leakage, establishing Vav3 as a regulator of endothelial barrier stability via DH-domain-dependent Rap1 activation. |
Endothelial cell gene expression correlation, ectopic Vav3 expression, DH domain mutant, Rap1 activation assay, barrier resistance measurement, in vivo Vav3 inactivation/vascular permeability assay |
The Journal of cell biology |
High |
29858212
|
| 2009 |
Vav3 controls vascular smooth muscle cell (VSMC) proliferation and migration through Rac1/PAK signaling. Vav3 catalytic activity (GEF function) is required for its effect on proliferation; co-expression of dominant-negative Rac1-N17 blocks the proliferative effect. Vav3 overexpression induces Rac1 membrane enrichment and PAK activation. |
siRNA silencing screen of 27 Rho GEFs, Vav3 overexpression and catalytic mutant, dominant-negative Rac1, PAK activation assay, proliferation/migration assays, in vivo stented artery model |
Cardiovascular research |
High |
19969623
|
| 2014 |
Phosphorylation of Tyr426 (equivalent site) in chicken 3BP2 by Syk is required for the inducible interaction of 3BP2 with the SH2 domain of Vav3. Loss of this phosphorylation reduces BCR-mediated Rac1 activation, placing 3BP2-Vav3 interaction as a link between Syk and Rac1 activation. |
Mutational analysis of 3BP2 phospho-sites, co-immunoprecipitation with Vav3 SH2 domain, Rac1 activation assay in DT40 B cells |
Experimental cell research |
Medium |
24406398
|
| 2018 |
In the context of oligodendrocyte biology, Vav3 deficiency accelerates OPC differentiation toward mature oligodendrocytes but reduces myelination capacity; remyelination is impaired in Vav3 knockout cerebellar slices and cuprizone-lesioned mice. FRET biosensors reveal altered RhoA GTPase activation profile in Vav3-deficient oligodendrocytes. |
Vav3 knockout mice, OPC differentiation assay, myelination of synthetic microfibers, lysolecithin demyelination of cerebellar slices, cuprizone model, FRET-based Rho GTPase biosensors |
Glia |
High |
30450647
|
| 2020 |
ERBB4 interacts with VAV3 via its kinase activity and phosphorylation of Tyr-1022 and Tyr-1162, with the intact VAV3 SH2 domain required for binding. ERBB4 stimulates tyrosine phosphorylation of the VAV3 activation domain (required for GEF activity). Active VAV3 mediates ERBB4-stimulated breast cancer cell migration. VAV1 and VAV2 also co-precipitate with ERBB4. |
MS-based interactome analysis, targeted MS, co-immunoprecipitation, ERBB4 kinase mutants, ERBB4 phospho-site mutants, SH2 domain mutant 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 exposed, and increases fibronectin deposition. These luminal Vav3/β1-integrin/fibronectin microdomains mediate enhanced Pseudomonas aeruginosa adhesion to the CF epithelium. Vav3 inhibition normalizes fibronectin/β1-integrin expression, improves CF epithelial integrity, and prevents bacterial trapping. |
RNA-seq, functional overexpression and siRNA knockdown, co-localization imaging, bacterial adhesion assay, fibronectin/integrin expression analysis |
Cell reports |
High |
32640241
|
| 2021 |
The small molecule IODVA1 binds directly to VAV3 and inhibits RAC activation and downstream signaling. In Vav3-null cells and animals, IODVA1 shows no activity, confirming VAV3 as its specific target. IODVA1 inhibits BCR-ABL1-driven leukemia cell proliferation and survival in a VAV3-dependent manner, overcoming TKI resistance. |
Small-molecule binding to VAV3, Vav3-null genetic control, RAC activation assay, BCR-ABL1 leukemia models in vitro and in vivo, patient-derived xenografts |
Leukemia |
High |
34711926
|
| 2022 |
In BCR-ABL B-ALL, Vav3 translocates predominantly to the nucleus where it interacts with BCR-ABL, Rac, and PRC1 proteins Bmi1, Ring1b, and Ezh2. The GEF activity of Vav3 is required for Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, interaction with Bmi1, and mono-ubiquitination of H2A(K119). Mechanistically, nuclear Vav3 prevents Phlpp2-sensitive Akt(S473)-dependent phosphorylation of Bmi1 at S314, which promotes leukemic B-cell progenitor transcriptional reprogramming. |
Nuclear fractionation, co-immunoprecipitation of nuclear Vav3 complexes, GEF-dead mutant functional assays, H2AK119Ub ChIP, Akt/Phlpp2/Bmi1 phosphorylation analysis, proliferation and self-renewal assays in Vav3-null leukemia model |
Nature communications |
High |
35650206
|
| 2023 |
HuR accumulates in the cytoplasm of CF airway epithelial cells, binds to and stabilizes Vav3 mRNA, causing Vav3 overexpression. Disruption of the HuR-Vav3 mRNA interaction improves CF epithelial integrity, inhibits fibronectin-based bacterial docking platforms, and prevents P. aeruginosa adhesion. |
RNA-seq, RIP (RNA immunoprecipitation) for HuR-Vav3 mRNA binding, HuR-Vav3 interaction disruption, epithelial integrity and bacterial adhesion assays |
JCI insight |
Medium |
36602863
|
| 2024 |
DDX5 binds VAV3 mRNA and facilitates its N6-methyladenosine (m6A) modification by interacting with the methyltransferase METTL3; m6A-modified VAV3 mRNA is then recognized by IGF2BP1, increasing mRNA stability and VAV3 expression in esophageal squamous cell carcinoma. |
RIP for DDX5-VAV3 mRNA binding, METTL3 interaction assays, m6A modification of VAV3 mRNA, IGF2BP1 recognition of m6A-VAV3, mRNA stability assays |
Oncogene |
Medium |
39289531
|
| 2024 |
STAT3 activation by high-fat diet (HFD) acts as a transcriptional factor to suppress VAV3 expression in liver. VAV3 deficiency retards GLUT4 membrane translocation and impairs glucose homeostasis; VAV3 also participates in cholesterol metabolism in hepatocytes. rAAV8-mediated VAV3 overexpression improves glucose homeostasis and attenuates hepatic cholesterol accumulation in HFD-fed mice. |
HFD mouse model, STAT3 transcriptional assay, GLUT4 vesicle trafficking assay, glucose uptake/homeostasis measurements, VAV3 rescue by rAAV8 vector |
International journal of biological sciences |
Medium |
38617550
|
| 2025 |
Bcl11a directly regulates Vav3 as a downstream transcriptional target in cerebellar Purkinje cells. Conditional Bcl11a deletion reduces Vav3 expression, and Vav3 overexpression partially rescues Purkinje cell dysfunction, dendritic morphology, and abnormal motor/social behaviors in Bcl11a-deficient mice. |
Conditional Purkinje cell-specific Bcl11a knockout, Vav3 overexpression rescue, behavioral assays (motor, social), electrophysiology, dendritic morphology analysis |
Molecular psychiatry |
High |
40855003
|
| 2025 |
Spleen tyrosine kinase (SYK) promotes Vav3 phosphorylation in osteoclasts; SYK and Vav3 colocalize at the leading edge of osteoclasts. SYK knockdown reduces Vav3 phosphorylation, abolishes SYK/Vav3 enrichment at the leading edge, decreases actin ring formation, and attenuates bone resorption. |
Co-localization imaging, SYK knockdown, Western blot for p-Vav3, bone resorption lacunae assay, actin ring formation assay, ACPA+ IgG stimulation of osteoclasts |
Cell biology international |
Medium |
40787875
|