{"gene":"VAV3","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":1999,"finding":"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.","method":"In vitro nucleotide exchange assays, co-precipitation with nucleotide-free GTPases, loss-of-function mutations in DH/PH/ZF domains, actin cytoskeleton imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro exchange assay with domain mutagenesis, multiple orthogonal methods in a single rigorous study","pmids":["10523675"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Transient expression of Vav3 truncation mutants, actin immunofluorescence, multinucleation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — domain dissection with clear morphological readouts, replicated in subsequent studies","pmids":["10523675"],"is_preprint":false},{"year":2000,"finding":"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).","method":"Co-immunoprecipitation, GST-fusion GTPase-binding domain pulldown assays, in vitro binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal pulldowns plus functional GTPase activation assays, multiple receptor systems tested","pmids":["11094073"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Cell-cycle synchronization, Western blot, enforced expression, dominant-negative RhoA epistasis, Y173 phosphorylation mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with RhoA, site-directed mutagenesis, cell-cycle fractionation","pmids":["11917103"],"is_preprint":false},{"year":2002,"finding":"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.","method":"B cell line Vav3 knockout, dominant-negative Rac1 expression, SHIP deletion epistasis, PIP3 measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (SHIP rescue), multiple signaling readouts, clean KO model","pmids":["11805146"],"is_preprint":false},{"year":2002,"finding":"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.","method":"PI3K/MAPK inhibitors, dominant-negative GTPase mutants, focus/colony formation assays, cell motility assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological and genetic epistasis approaches dissecting downstream pathways","pmids":["11884391"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation, domain-mapping pulldowns, focus formation assays, kinase assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — domain-mapped interaction with functional validation by focus formation","pmids":["12400014"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Vav3 knockout mice, actin staining, bone resorption assays, genetic/biochemical epistasis with Syk","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific cellular phenotypes plus epistasis identifying upstream kinase","pmids":["15711558"],"is_preprint":false},{"year":2005,"finding":"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.","method":"FRET-based activity imaging, RNAi knockdown, live-cell imaging of PIP3 and GTPase activity","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — FRET biosensors plus RNAi with real-time imaging; multiple orthogonal methods","pmids":["15728722"],"is_preprint":false},{"year":2005,"finding":"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.","method":"SH2 point mutation, domain deletions, co-immunoprecipitation, T cell-deficient lines, NFAT reporter assays, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple T cell-deficient lines, site-directed mutagenesis, localization and functional assays","pmids":["15708849"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Single-particle electron microscopy of unphosphorylated, phosphorylated, and N-terminally truncated Vav3 proteins","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — direct structural analysis with three functional states compared","pmids":["15775967"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Reporter gene assays, Vav3 knockdown, domain deletion/mutation, co-immunoprecipitation","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — multiple domain mutants, GEF-dead controls, functional reporter assays","pmids":["16384856"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Vav3 knockout mice, pharmacological epistasis with adrenergic/RAS blockers, catecholamine measurements, cardiovascular phenotyping","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — KO model with pharmacological epistasis establishing pathway hierarchy","pmids":["16767097"],"is_preprint":false},{"year":2006,"finding":"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.","method":"DH domain deletion, AR reporter assays, PI3K inhibitors, dominant-negative Akt, Western blot for pAkt","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — domain mapping plus pharmacological epistasis with functional growth assays","pmids":["16762975"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Co-immunoprecipitation of endogenous complex, SH2-mutant Vav3, Vav3-specific shRNA, dominant-negative Rac1, Rac1 activation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IPs mapping binding site, shRNA loss-of-function with invasion assay, patient biopsy validation","pmids":["17998938"],"is_preprint":false},{"year":2008,"finding":"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.","method":"GST pull-down, co-immunoprecipitation, ERα reporter assays, domain deletions, PI3K inhibitors, siRNA knockdown","journal":"BMC cancer","confidence":"High","confidence_rationale":"Tier 2 — direct physical interaction by GST pulldown plus functional domain mapping","pmids":["18518979"],"is_preprint":false},{"year":2009,"finding":"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.","method":"ChIP demonstrating AhR recruitment to vav3 promoter, Vav3 siRNA, Vav3-/- MEFs, Rac1 activity assays, pharmacological Rac1 and ROCK inhibitors, actin/adhesion imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP establishes direct transcriptional regulation; multiple orthogonal methods confirm downstream signaling","pmids":["19158396"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA screen of 27 Rho GEFs, Vav3 overexpression, catalytic mutant, Src inhibitor SU6656, dominant-negative Rac1-N17, PAK activation assay, membrane fractionation","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — functional screen, catalytic mutant control, epistasis with Src and dominant-negative Rac1","pmids":["19969623"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Ahr-/- and Vav3-/- mouse comparison, RT-PCR/Western blot tissue expression, electrophysiology of ventrolateral medulla","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — parallel phenotypic comparison of two KO mouse lines with shared pathway placement","pmids":["21115475"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Vav3 knockout mice, histological analysis, primary Purkinje/granule cell cultures, motor coordination tests","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific cellular phenotypes and in vitro neuronal culture validation","pmids":["20089829"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Sequential chromatin immunoprecipitation (ChIP), membrane/nuclear targeting constructs, subcellular fractionation, AR reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — sequential ChIP plus compartment-targeting experiments; multiple orthogonal methods","pmids":["21765461"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation of AR3-Vav3, nuclear fractionation, Vav3 knockdown, AR reporter assays, soft-agar growth","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — physical interaction plus nuclear localization data and functional growth assays","pmids":["23023561"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Vav3 KO mouse model of BCR-ABL leukemia, epistasis with Rac2-/-, apoptosis assays, GTPase activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with epistasis and mechanistic signaling readouts","pmids":["22692505"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, AR reporter assays, AR N-C interaction assay, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — interaction confirmed by multiple methods with functional domain-disruption validation","pmids":["23281476"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation of EphA2-Vav3, Rac1 activation assay, Vav3 siRNA, in vivo metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — receptor-GEF interaction with functional Rac1 activation and in vivo validation","pmids":["22659453"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Site-directed mutagenesis of 3BP2 tyrosines, co-immunoprecipitation of 3BP2-Vav3 SH2, Rac1 activation assay in DT40 cells","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — phosphosite mutagenesis with interaction and downstream GTPase activation assay","pmids":["24406398"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Proteomics/MS identification of TRAF6 interactors, GST pulldown domain mapping, co-immunoprecipitation, RANK cytoplasmic tail mutants, downstream signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — MS discovery confirmed by domain-mapped GST pulldown and reciprocal co-IP with functional mutants","pmids":["27507811"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Endothelial gene expression correlation, Vav3 ectopic expression, DH domain mutants, Rap1 activation assay, transendothelial resistance measurements, in vivo vascular permeability assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — domain mutant, downstream GTPase identification (Rap1), and in vivo vascular phenotype","pmids":["29858212"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Vav3 KO mice, OPC differentiation assay, myelination assay on synthetic fibers, lysolecithin/cuprizone demyelination models, FRET-based RhoA biosensors","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 — KO model with multiple functional assays and FRET-based mechanistic readout","pmids":["30450647"],"is_preprint":false},{"year":2020,"finding":"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.","method":"MS-based proteomics, targeted MS, co-immunoprecipitation, site-directed mutagenesis of ERBB4/VAV3, dominant-negative VAV3, shRNA knockdown, migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — MS discovery confirmed by co-IP with mutagenesis and phosphorylation of activation domain validated","pmids":["32561640"],"is_preprint":false},{"year":2020,"finding":"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.","method":"RNA-seq, immunofluorescence/apical localization imaging, Vav3 knockdown, fibronectin deposition assay, bacterial adhesion assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — mechanistic localization study with functional KD readout on bacterial adhesion","pmids":["32640241"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Small-molecule binding assay, Vav3 KO epistasis, RAC activation assay, murine and patient-derived xenograft models","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — genetic null controls confirm target specificity; multiple model systems","pmids":["34711926"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation of nuclear Vav3 with PRC1 components, GEF-dead mutant, nuclear fractionation, ChIP for H2AK119Ub, Bmi1 phosphorylation/mutagenesis, Vav3 KO leukemia models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (co-IP, ChIP, genetic KO, mutagenesis) across nuclear signaling pathway","pmids":["35650206"],"is_preprint":false},{"year":2023,"finding":"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.","method":"RNA immunoprecipitation (RIP) of HuR-Vav3 mRNA, HuR-Vav3 interaction disruption, epithelial integrity assays, bacterial adhesion assay","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — RIP establishes direct mRNA-protein interaction; functional disruption with clear readout","pmids":["36602863"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP/reporter for STAT3 on VAV3 promoter, VAV3 KO, GLUT4 translocation imaging, glucose uptake assay, AAV rescue in vivo","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 — transcriptional regulation confirmed by ChIP; functional GLUT4 and cholesterol assays with in vivo AAV rescue","pmids":["38617550"],"is_preprint":false},{"year":2017,"finding":"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.","method":"DNMT3B overexpression in HaCaT cells, methylation-specific analysis of VAV3 promoter, gene expression microarray and RT-PCR","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — single lab, methylation assay plus expression readout; no rescue experiment","pmids":["28123849"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Vav single and double knockout mice, GPVI stimulation, PLCγ2 phosphorylation assay, platelet aggregation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean double KO genetic epistasis demonstrating absolute redundancy with specific signaling readout","pmids":["15456756"],"is_preprint":false},{"year":2017,"finding":"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.","method":"C1 domain mutagenesis, phorbol ester binding assay, GEF activity assay, membrane localization imaging","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro binding assay plus mutagenesis and functional GEF assay; single lab","pmids":["28927664"],"is_preprint":false},{"year":2025,"finding":"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.","method":"SYK shRNA knockdown, Western blot for pVav3/pSYK, colocalization imaging (phalloidin/WGA staining), bone resorption lacunae assay","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — colocalization plus functional KD with phosphorylation and resorption readouts; single lab","pmids":["40787875"],"is_preprint":false}],"current_model":"VAV3 is a tyrosine phosphorylation-regulated GDP/GTP exchange factor (GEF) for Rho-family GTPases (primarily RhoA, RhoG, Rac1, Cdc42) whose autoinhibitory calponin-homology/acidic domain keeps it inactive until phosphorylation by upstream tyrosine kinases (including Syk, Src-family kinases, and receptor tyrosine kinases such as EGFR, ERBB4, EphA2, and M-CSF-R) induces global conformational rearrangements that open the DH-PH catalytic core; activated VAV3 drives actin cytoskeletal remodeling (stress fibers, lamellipodia, filopodia), regulates cytokinesis via RhoA, controls cell migration via Rac1/PAK, and localizes to the nucleus—through a PH domain-dependent mechanism—where it acts as a GEF-independent coactivator of androgen and estrogen receptors, interacts with PRC1 components (Bmi1, Ring1b) to regulate H2AK119 ubiquitination, and integrates signals from multiple upstream adaptors (SLP-76, APS, 3BP2, TRAF6, Cdc37, HuR)."},"narrative":{"teleology":[{"year":1999,"claim":"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","pmids":["10523675"],"confidence":"High","gaps":["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"]},{"year":2000,"claim":"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","pmids":["11094073"],"confidence":"High","gaps":["Which specific tyrosines on VAV3 are phosphorylated by each receptor not mapped","Whether all receptor interactions are direct or adaptor-mediated not resolved"]},{"year":2002,"claim":"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","pmids":["11917103","11805146","11884391","12400014"],"confidence":"High","gaps":["Whether APS-mediated relief of autoinhibition operates in non-transformed cells unknown","Relative contribution of PI3K vs. direct GTPase pathways to transformation not quantified"]},{"year":2004,"claim":"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","pmids":["15456756"],"confidence":"High","gaps":["Whether Vav3 contributes to GPVI signaling independently of Vav1 remains unclear","GTPase substrate utilized in platelet context not identified"]},{"year":2005,"claim":"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","pmids":["15775967","15711558","15728722","15708849","16384856"],"confidence":"High","gaps":["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"]},{"year":2006,"claim":"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","pmids":["16762975","16767097"],"confidence":"High","gaps":["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"]},{"year":2009,"claim":"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","pmids":["19158396","19969623"],"confidence":"High","gaps":["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"]},{"year":2010,"claim":"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","pmids":["21115475","20089829"],"confidence":"High","gaps":["GTPase substrate for dendritogenesis not identified","Whether AhR-Vav3 circuit operates cell-autonomously in neurons unknown"]},{"year":2011,"claim":"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","pmids":["21765461"],"confidence":"High","gaps":["Nuclear import mechanism not identified (no NLS mapped)","Whether nuclear VAV3 has additional chromatin targets beyond AR not explored"]},{"year":2012,"claim":"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","pmids":["23023561","22692505","23281476","22659453"],"confidence":"High","gaps":["How Cdc37 enhances VAV3 coactivator function mechanistically not clear","Whether EphA2-Vav3 interaction is direct or mediated by intermediate adaptors not resolved"]},{"year":2016,"claim":"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","pmids":["27507811"],"confidence":"High","gaps":["Whether TRAF6 binding affects VAV3 GEF activity directly not tested","Role in non-osteoclast RANK-expressing cells unknown"]},{"year":2018,"claim":"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","pmids":["29858212","30450647"],"confidence":"High","gaps":["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"]},{"year":2020,"claim":"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","pmids":["32561640","32640241"],"confidence":"High","gaps":["Whether VAV3 GEF activity is required for CF phenotype not tested","Downstream GTPase target in CF epithelium not identified"]},{"year":2021,"claim":"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","pmids":["34711926"],"confidence":"High","gaps":["Binding site on VAV3 not structurally defined","Off-target effects on other Vav family members not excluded"]},{"year":2022,"claim":"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","pmids":["35650206"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["36602863"],"confidence":"High","gaps":["Specific AU-rich element in Vav3 mRNA bound by HuR not mapped","Whether HuR-Vav3 mRNA regulation operates in non-CF contexts unknown"]},{"year":2024,"claim":"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","pmids":["38617550"],"confidence":"High","gaps":["GTPase substrate mediating GLUT4 vesicle translocation not identified","Whether this function is GEF-dependent or -independent not tested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,8,17,27,28]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,15,20,21,32]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,7,30]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[20,21,32]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,9,27,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5,8,17,24,27,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,9,25,36]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,22,31]}],"complexes":["RANK-TRAF6-VAV3 signaling complex","NPM-ALK-Src-Vav3 complex"],"partners":["RHOA","RAC1","SYK","TRAF6","SLP76","ERBB4","BMI1","CDC37"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q9UKW4","full_name":"Guanine nucleotide exchange factor VAV3","aliases":[],"length_aa":847,"mass_kda":97.8,"function":"Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1. Binds physically to the nucleotide-free states of those GTPases. Plays an important role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly (By similarity). May be important for integrin-mediated signaling, at least in some cell types. In osteoclasts, along with SYK tyrosine kinase, required for signaling through integrin alpha-v/beta-1 (ITAGV-ITGB1), a crucial event for osteoclast proper cytoskeleton organization and function. This signaling pathway involves RAC1, but not RHO, activation. Necessary for proper wound healing. In the course of wound healing, required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Responsible for integrin beta-2 (ITGB2)-mediated macrophage adhesion and, to a lesser extent, contributes to beta-3 (ITGB3)-mediated adhesion. Does not affect integrin beta-1 (ITGB1)-mediated adhesion (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UKW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VAV3","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VAV3","total_profiled":1310},"omim":[{"mim_id":"616347","title":"PR DOMAIN-CONTAINING PROTEIN 11; PRDM11","url":"https://www.omim.org/entry/616347"},{"mim_id":"605541","title":"VAV GUANINE NUCLEOTIDE EXCHANGE FACTOR 3; VAV3","url":"https://www.omim.org/entry/605541"},{"mim_id":"604213","title":"CHUDLEY-MCCULLOUGH SYNDROME; CMCS","url":"https://www.omim.org/entry/604213"},{"mim_id":"600428","title":"VAV GUANINE NUCLEOTIDE EXCHANGE FACTOR 2; VAV2","url":"https://www.omim.org/entry/600428"},{"mim_id":"600085","title":"PROTEIN-TYROSINE KINASE SYK; SYK","url":"https://www.omim.org/entry/600085"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":78.4}],"url":"https://www.proteinatlas.org/search/VAV3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9UKW4","domains":[{"cath_id":"1.10.418.10","chopping":"4-149","consensus_level":"high","plddt":89.8309,"start":4,"end":149},{"cath_id":"1.20.900.10","chopping":"191-376","consensus_level":"high","plddt":94.1416,"start":191,"end":376},{"cath_id":"2.30.29.30","chopping":"391-505","consensus_level":"medium","plddt":89.2915,"start":391,"end":505},{"cath_id":"3.30.60.20","chopping":"512-559","consensus_level":"medium","plddt":93.4106,"start":512,"end":559},{"cath_id":"2.30.30.40","chopping":"597-658","consensus_level":"medium","plddt":84.2532,"start":597,"end":658},{"cath_id":"3.30.505.10","chopping":"674-766","consensus_level":"high","plddt":86.9075,"start":674,"end":766},{"cath_id":"2.30.30.40","chopping":"792-846","consensus_level":"high","plddt":80.5938,"start":792,"end":846}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKW4-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VAV3","jax_strain_url":"https://www.jax.org/strain/search?query=VAV3"},"sequence":{"accession":"Q9UKW4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKW4"}},"corpus_meta":[{"pmid":"10523675","id":"PMC_10523675","title":"Biological 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and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11094073","citation_count":126,"is_preprint":false},{"pmid":"15728722","id":"PMC_15728722","title":"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.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15728722","citation_count":124,"is_preprint":false},{"pmid":"11805146","id":"PMC_11805146","title":"Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation.","date":"2002","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11805146","citation_count":115,"is_preprint":false},{"pmid":"23033540","id":"PMC_23033540","title":"The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells.","date":"2012","source":"Science 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regulating the expression of the Vav3 proto-oncogene.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21115475","citation_count":54,"is_preprint":false},{"pmid":"17998938","id":"PMC_17998938","title":"Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17998938","citation_count":49,"is_preprint":false},{"pmid":"20140222","id":"PMC_20140222","title":"VAV2 and VAV3 as candidate disease genes for spontaneous glaucoma in mice and humans.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20140222","citation_count":48,"is_preprint":false},{"pmid":"23023561","id":"PMC_23023561","title":"Vav3 enhances androgen receptor splice variant activity and is critical for castration-resistant prostate cancer growth and survival.","date":"2012","source":"Molecular endocrinology (Baltimore, 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co-precipitation with nucleotide-free GTPases, loss-of-function mutations in DH/PH/ZF domains, actin cytoskeleton imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro exchange assay with domain mutagenesis, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"10523675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Transient expression of Vav3 truncation mutants, actin immunofluorescence, multinucleation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain dissection with clear morphological readouts, replicated in subsequent studies\",\n      \"pmids\": [\"10523675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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).\",\n      \"method\": \"Co-immunoprecipitation, GST-fusion GTPase-binding domain pulldown assays, in vitro binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldowns plus functional GTPase activation assays, multiple receptor systems tested\",\n      \"pmids\": [\"11094073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-cycle synchronization, Western blot, enforced expression, dominant-negative RhoA epistasis, Y173 phosphorylation mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with RhoA, site-directed mutagenesis, cell-cycle fractionation\",\n      \"pmids\": [\"11917103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"B cell line Vav3 knockout, dominant-negative Rac1 expression, SHIP deletion epistasis, PIP3 measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (SHIP rescue), multiple signaling readouts, clean KO model\",\n      \"pmids\": [\"11805146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"PI3K/MAPK inhibitors, dominant-negative GTPase mutants, focus/colony formation assays, cell motility assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic epistasis approaches dissecting downstream pathways\",\n      \"pmids\": [\"11884391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldowns, focus formation assays, kinase assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-mapped interaction with functional validation by focus formation\",\n      \"pmids\": [\"12400014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Vav3 knockout mice, actin staining, bone resorption assays, genetic/biochemical epistasis with Syk\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific cellular phenotypes plus epistasis identifying upstream kinase\",\n      \"pmids\": [\"15711558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"FRET-based activity imaging, RNAi knockdown, live-cell imaging of PIP3 and GTPase activity\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — FRET biosensors plus RNAi with real-time imaging; multiple orthogonal methods\",\n      \"pmids\": [\"15728722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"SH2 point mutation, domain deletions, co-immunoprecipitation, T cell-deficient lines, NFAT reporter assays, confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple T cell-deficient lines, site-directed mutagenesis, localization and functional assays\",\n      \"pmids\": [\"15708849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Single-particle electron microscopy of unphosphorylated, phosphorylated, and N-terminally truncated Vav3 proteins\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural analysis with three functional states compared\",\n      \"pmids\": [\"15775967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter gene assays, Vav3 knockdown, domain deletion/mutation, co-immunoprecipitation\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple domain mutants, GEF-dead controls, functional reporter assays\",\n      \"pmids\": [\"16384856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Vav3 knockout mice, pharmacological epistasis with adrenergic/RAS blockers, catecholamine measurements, cardiovascular phenotyping\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with pharmacological epistasis establishing pathway hierarchy\",\n      \"pmids\": [\"16767097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"DH domain deletion, AR reporter assays, PI3K inhibitors, dominant-negative Akt, Western blot for pAkt\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping plus pharmacological epistasis with functional growth assays\",\n      \"pmids\": [\"16762975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of endogenous complex, SH2-mutant Vav3, Vav3-specific shRNA, dominant-negative Rac1, Rac1 activation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IPs mapping binding site, shRNA loss-of-function with invasion assay, patient biopsy validation\",\n      \"pmids\": [\"17998938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, ERα reporter assays, domain deletions, PI3K inhibitors, siRNA knockdown\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct physical interaction by GST pulldown plus functional domain mapping\",\n      \"pmids\": [\"18518979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP demonstrating AhR recruitment to vav3 promoter, Vav3 siRNA, Vav3-/- MEFs, Rac1 activity assays, pharmacological Rac1 and ROCK inhibitors, actin/adhesion imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP establishes direct transcriptional regulation; multiple orthogonal methods confirm downstream signaling\",\n      \"pmids\": [\"19158396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA screen of 27 Rho GEFs, Vav3 overexpression, catalytic mutant, Src inhibitor SU6656, dominant-negative Rac1-N17, PAK activation assay, membrane fractionation\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional screen, catalytic mutant control, epistasis with Src and dominant-negative Rac1\",\n      \"pmids\": [\"19969623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Ahr-/- and Vav3-/- mouse comparison, RT-PCR/Western blot tissue expression, electrophysiology of ventrolateral medulla\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parallel phenotypic comparison of two KO mouse lines with shared pathway placement\",\n      \"pmids\": [\"21115475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Vav3 knockout mice, histological analysis, primary Purkinje/granule cell cultures, motor coordination tests\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific cellular phenotypes and in vitro neuronal culture validation\",\n      \"pmids\": [\"20089829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Sequential chromatin immunoprecipitation (ChIP), membrane/nuclear targeting constructs, subcellular fractionation, AR reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — sequential ChIP plus compartment-targeting experiments; multiple orthogonal methods\",\n      \"pmids\": [\"21765461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of AR3-Vav3, nuclear fractionation, Vav3 knockdown, AR reporter assays, soft-agar growth\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction plus nuclear localization data and functional growth assays\",\n      \"pmids\": [\"23023561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Vav3 KO mouse model of BCR-ABL leukemia, epistasis with Rac2-/-, apoptosis assays, GTPase activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with epistasis and mechanistic signaling readouts\",\n      \"pmids\": [\"22692505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, AR reporter assays, AR N-C interaction assay, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by multiple methods with functional domain-disruption validation\",\n      \"pmids\": [\"23281476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of EphA2-Vav3, Rac1 activation assay, Vav3 siRNA, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — receptor-GEF interaction with functional Rac1 activation and in vivo validation\",\n      \"pmids\": [\"22659453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of 3BP2 tyrosines, co-immunoprecipitation of 3BP2-Vav3 SH2, Rac1 activation assay in DT40 cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phosphosite mutagenesis with interaction and downstream GTPase activation assay\",\n      \"pmids\": [\"24406398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics/MS identification of TRAF6 interactors, GST pulldown domain mapping, co-immunoprecipitation, RANK cytoplasmic tail mutants, downstream signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS discovery confirmed by domain-mapped GST pulldown and reciprocal co-IP with functional mutants\",\n      \"pmids\": [\"27507811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Endothelial gene expression correlation, Vav3 ectopic expression, DH domain mutants, Rap1 activation assay, transendothelial resistance measurements, in vivo vascular permeability assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutant, downstream GTPase identification (Rap1), and in vivo vascular phenotype\",\n      \"pmids\": [\"29858212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Vav3 KO mice, OPC differentiation assay, myelination assay on synthetic fibers, lysolecithin/cuprizone demyelination models, FRET-based RhoA biosensors\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model with multiple functional assays and FRET-based mechanistic readout\",\n      \"pmids\": [\"30450647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"MS-based proteomics, targeted MS, co-immunoprecipitation, site-directed mutagenesis of ERBB4/VAV3, dominant-negative VAV3, shRNA knockdown, migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS discovery confirmed by co-IP with mutagenesis and phosphorylation of activation domain validated\",\n      \"pmids\": [\"32561640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq, immunofluorescence/apical localization imaging, Vav3 knockdown, fibronectin deposition assay, bacterial adhesion assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic localization study with functional KD readout on bacterial adhesion\",\n      \"pmids\": [\"32640241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Small-molecule binding assay, Vav3 KO epistasis, RAC activation assay, murine and patient-derived xenograft models\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null controls confirm target specificity; multiple model systems\",\n      \"pmids\": [\"34711926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of nuclear Vav3 with PRC1 components, GEF-dead mutant, nuclear fractionation, ChIP for H2AK119Ub, Bmi1 phosphorylation/mutagenesis, Vav3 KO leukemia models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (co-IP, ChIP, genetic KO, mutagenesis) across nuclear signaling pathway\",\n      \"pmids\": [\"35650206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of HuR-Vav3 mRNA, HuR-Vav3 interaction disruption, epithelial integrity assays, bacterial adhesion assay\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RIP establishes direct mRNA-protein interaction; functional disruption with clear readout\",\n      \"pmids\": [\"36602863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP/reporter for STAT3 on VAV3 promoter, VAV3 KO, GLUT4 translocation imaging, glucose uptake assay, AAV rescue in vivo\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional regulation confirmed by ChIP; functional GLUT4 and cholesterol assays with in vivo AAV rescue\",\n      \"pmids\": [\"38617550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"DNMT3B overexpression in HaCaT cells, methylation-specific analysis of VAV3 promoter, gene expression microarray and RT-PCR\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab, methylation assay plus expression readout; no rescue experiment\",\n      \"pmids\": [\"28123849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Vav single and double knockout mice, GPVI stimulation, PLCγ2 phosphorylation assay, platelet aggregation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean double KO genetic epistasis demonstrating absolute redundancy with specific signaling readout\",\n      \"pmids\": [\"15456756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"C1 domain mutagenesis, phorbol ester binding assay, GEF activity assay, membrane localization imaging\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding assay plus mutagenesis and functional GEF assay; single lab\",\n      \"pmids\": [\"28927664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"SYK shRNA knockdown, Western blot for pVav3/pSYK, colocalization imaging (phalloidin/WGA staining), bone resorption lacunae assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — colocalization plus functional KD with phosphorylation and resorption readouts; single lab\",\n      \"pmids\": [\"40787875\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VAV3 is a tyrosine phosphorylation-regulated GDP/GTP exchange factor (GEF) for Rho-family GTPases (primarily RhoA, RhoG, Rac1, Cdc42) whose autoinhibitory calponin-homology/acidic domain keeps it inactive until phosphorylation by upstream tyrosine kinases (including Syk, Src-family kinases, and receptor tyrosine kinases such as EGFR, ERBB4, EphA2, and M-CSF-R) induces global conformational rearrangements that open the DH-PH catalytic core; activated VAV3 drives actin cytoskeletal remodeling (stress fibers, lamellipodia, filopodia), regulates cytokinesis via RhoA, controls cell migration via Rac1/PAK, and localizes to the nucleus—through a PH domain-dependent mechanism—where it acts as a GEF-independent coactivator of androgen and estrogen receptors, interacts with PRC1 components (Bmi1, Ring1b) to regulate H2AK119 ubiquitination, and integrates signals from multiple upstream adaptors (SLP-76, APS, 3BP2, TRAF6, Cdc37, HuR).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro nucleotide exchange assays with domain mutants, co-precipitation with nucleotide-free GTPases, actin cytoskeleton and multinucleation imaging in transfected cells\",\n      \"pmids\": [\"10523675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation and GST-pulldown with stimulated receptors, GTPase-binding domain assays for Rac1/Cdc42/RhoA activation\",\n      \"pmids\": [\"11094073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific tyrosines on VAV3 are phosphorylated by each receptor not mapped\", \"Whether all receptor interactions are direct or adaptor-mediated not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"11917103\", \"11805146\", \"11884391\", \"12400014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APS-mediated relief of autoinhibition operates in non-transformed cells unknown\", \"Relative contribution of PI3K vs. direct GTPase pathways to transformation not quantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic redundancy between Vav1 and Vav3 in platelet GPVI-PLCγ2 signaling revealed that VAV3 participates in hemostatic signaling beyond lymphocytes.\",\n      \"evidence\": \"Vav1/Vav3 single and double KO platelets with GPVI stimulation, PLCγ2 phosphorylation, and aggregation assays\",\n      \"pmids\": [\"15456756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Vav3 contributes to GPVI signaling independently of Vav1 remains unclear\", \"GTPase substrate utilized in platelet context not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"15775967\", \"15711558\", \"15728722\", \"15708849\", \"16384856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"16762975\", \"16767097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"19158396\", \"19969623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Parallel phenotyping of Ahr−/− and Vav3−/− mice with shared cardiorespiratory and GABAergic phenotypes; Vav3 KO histology, primary neuronal cultures, motor coordination tests\",\n      \"pmids\": [\"21115475\", \"20089829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase substrate for dendritogenesis not identified\", \"Whether AhR-Vav3 circuit operates cell-autonomously in neurons unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Sequential ChIP, nuclear/membrane targeting constructs, subcellular fractionation, AR reporter assays\",\n      \"pmids\": [\"21765461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear import mechanism not identified (no NLS mapped)\", \"Whether nuclear VAV3 has additional chromatin targets beyond AR not explored\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"23023561\", \"22692505\", \"23281476\", \"22659453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Cdc37 enhances VAV3 coactivator function mechanistically not clear\", \"Whether EphA2-Vav3 interaction is direct or mediated by intermediate adaptors not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS-based proteomics, GST pulldown domain mapping, reciprocal co-IP, RANK cytoplasmic tail mutants, downstream signaling assays\",\n      \"pmids\": [\"27507811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRAF6 binding affects VAV3 GEF activity directly not tested\", \"Role in non-osteoclast RANK-expressing cells unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Rap1 activation assay with DH mutants, transendothelial resistance, in vivo permeability; Vav3 KO OPC differentiation, synthetic fiber myelination, FRET-based RhoA biosensors\",\n      \"pmids\": [\"29858212\", \"30450647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS-based proteomics with ERBB4 tyrosine mutagenesis, VAV3 SH2 mutant, shRNA, migration assays; RNA-seq, apical localization imaging, Vav3 KD, bacterial adhesion assay\",\n      \"pmids\": [\"32561640\", \"32640241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VAV3 GEF activity is required for CF phenotype not tested\", \"Downstream GTPase target in CF epithelium not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Small-molecule binding assay, Vav3 KO cells as negative control, RAC activation assay, murine and patient-derived xenograft models\",\n      \"pmids\": [\"34711926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on VAV3 not structurally defined\", \"Off-target effects on other Vav family members not excluded\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Nuclear co-IP of VAV3 with PRC1 components, GEF-dead mutant, ChIP for H2AK119Ub, Bmi1 S314 phosphorylation mutagenesis, Vav3 KO leukemia models\",\n      \"pmids\": [\"35650206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNA immunoprecipitation of HuR-Vav3 mRNA, HuR interaction disruption, epithelial integrity and bacterial adhesion assays\",\n      \"pmids\": [\"36602863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific AU-rich element in Vav3 mRNA bound by HuR not mapped\", \"Whether HuR-Vav3 mRNA regulation operates in non-CF contexts unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP and reporter assays for STAT3 on VAV3 promoter, VAV3 KO, GLUT4 translocation imaging, glucose uptake assay, AAV8-mediated VAV3 rescue in vivo\",\n      \"pmids\": [\"38617550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase substrate mediating GLUT4 vesicle translocation not identified\", \"Whether this function is GEF-dependent or -independent not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 8, 17, 27, 28]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 15, 20, 21, 32]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 7, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [20, 21, 32]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 9, 27, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5, 8, 17, 24, 27, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9, 25, 36]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-R-HSA-4839726\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 22, 31]}\n    ],\n    \"complexes\": [\n      \"RANK-TRAF6-VAV3 signaling complex\",\n      \"NPM-ALK-Src-Vav3 complex\"\n    ],\n    \"partners\": [\n      \"RHOA\",\n      \"RAC1\",\n      \"SYK\",\n      \"TRAF6\",\n      \"SLP76\",\n      \"ERBB4\",\n      \"BMI1\",\n      \"CDC37\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}