VAV3

Summary

VAV3 (vav guanine nucleotide exchange factor 3, HGNC:12659) is a protein-coding gene on chromosome 1p13.3, encoding Guanine nucleotide exchange factor VAV3 (Q9UKW4). Exchange factor for GTP-binding proteins RhoA, RhoG and, to a lesser extent, Rac1.

This gene is a member of the VAV gene family. The VAV proteins are guanine nucleotide exchange factors (GEFs) for Rho family GTPases that activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. This gene product acts as a GEF preferentially for RhoG, RhoA, and to a lesser extent, RAC1, and it associates maximally with the nucleotide-free states of these GTPases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 10451 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 166 total
• MANE Select transcript: NM_006113

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12659
Approved symbol	VAV3
Name	vav guanine nucleotide exchange factor 3
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134215
Ensembl biotype	protein_coding
OMIM	605541
Entrez	10451

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding_CDS_not_defined, 6 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000343258, ENST00000370056, ENST00000415432, ENST00000469325, ENST00000479977, ENST00000490388, ENST00000524574, ENST00000525231, ENST00000525460, ENST00000527011, ENST00000529033, ENST00000529413, ENST00000529809, ENST00000530671, ENST00000533398, ENST00000923907

RefSeq mRNA: 2 — MANE Select: NM_006113 NM_001079874, NM_006113

CCDS: CCDS44181, CCDS785

Canonical transcript exons

ENST00000370056 — 27 exons

Exon	Start	End
ENSE00001894713	107964666	107965180
ENSE00001902342	107571161	107573372
ENSE00003459483	107704960	107705061
ENSE00003461962	107688381	107688406
ENSE00003462627	107772735	107772843
ENSE00003482775	107770636	107770728
ENSE00003483559	107704550	107704650
ENSE00003497416	107574047	107574198
ENSE00003501742	107777231	107777296
ENSE00003516205	107642619	107642755
ENSE00003519148	107751117	107751202
ENSE00003529559	107755427	107755513
ENSE00003532265	107760784	107760879
ENSE00003553422	107766447	107766550
ENSE00003568698	107768441	107768509
ENSE00003587974	107603047	107603163
ENSE00003603497	107749462	107749594
ENSE00003617718	107748968	107749077
ENSE00003618647	107596212	107596341
ENSE00003623768	107765076	107765175
ENSE00003644980	107683488	107683533
ENSE00003649608	107617567	107617632
ENSE00003656913	107874901	107875017
ENSE00003666294	107779434	107779492
ENSE00003669471	107602397	107602484
ENSE00003686990	107609931	107609965
ENSE00003693923	107757261	107757329

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.4966 / max 582.1069, expressed in 1029 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13626	5.2958	862
13612	2.6264	261
13627	1.1383	442
13628	0.1684	83
13613	0.1562	86
13611	0.0562	34
13622	0.0347	19
13617	0.0206	10

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	99.55	gold quality
renal medulla	UBERON:0000362	98.89	gold quality
esophagus squamous epithelium	UBERON:0006920	98.52	gold quality
upper leg skin	UBERON:0004262	98.48	gold quality
gingival epithelium	UBERON:0001949	98.07	gold quality
skin of hip	UBERON:0001554	97.98	gold quality
secondary oocyte	CL:0000655	97.58	gold quality
gingiva	UBERON:0001828	97.23	gold quality
squamous epithelium	UBERON:0006914	97.18	gold quality
nephron tubule	UBERON:0001231	96.79	gold quality
tibia	UBERON:0000979	96.66	gold quality
epithelium of esophagus	UBERON:0001976	96.42	gold quality
rectum	UBERON:0001052	95.98	gold quality
palpebral conjunctiva	UBERON:0001812	95.83	gold quality
hair follicle	UBERON:0002073	95.53	gold quality
oral cavity	UBERON:0000167	95.48	gold quality
nipple	UBERON:0002030	95.24	gold quality
mammalian vulva	UBERON:0000997	94.97	gold quality
colonic mucosa	UBERON:0000317	94.18	gold quality
cervix squamous epithelium	UBERON:0006922	94.15	gold quality
placenta	UBERON:0001987	94.05	gold quality
skin of abdomen	UBERON:0001416	93.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.57	gold quality
zone of skin	UBERON:0000014	93.36	gold quality
adult mammalian kidney	UBERON:0000082	93.12	gold quality
renal glomerulus	UBERON:0000074	93.09	gold quality
kidney	UBERON:0002113	92.86	gold quality
oocyte	CL:0000023	92.77	gold quality
epithelium of nasopharynx	UBERON:0001951	92.60	gold quality
skin of leg	UBERON:0001511	92.56	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	52.26
E-HCAD-10	yes	23.10
E-ANND-3	yes	8.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, PRDM11

miRNA regulators (miRDB)

149 targeting VAV3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-548P	99.98	72.25	3784

Literature-anchored findings (GeneRIF, showing 40)

• Vav3 regulates the B cell responses by promoting the sustained production of PIP3 and thereby calcium flux (PMID:11805146)
• We present here a novel stimulatory mechanism of Vav3 in which APS directly relieves the autoinhibitory CH domain and furthermore enhances its tyrosine phosphorylation by Lck. (PMID:12400014)
• results demonstrate that Vav3 and Vav1 play crucial but redundant roles in the activation of phospholipase C gamma 2 by glycoprotein GPVI (PMID:15456756)
• TCR-induced association of Vav3 with SLP-76 is required for its membrane/IS localization and function (PMID:15708849)
• Vav3 levels rise during prostate cancer progression to androgen independence. (PMID:16384856)
• Vav3 oncogene is overexpressed and regulates cell growth and androgen receptor activity in human prostate cancer development and progression. (PMID:16762975)
• Constitutively active Vav3 mediates ligand-independent transcriptional activation and promotes nuclear localization pf the androgen receptor in prostate neoplsms. (PMID:18079321)
• Findings suggest that Vav3 overexpression may aberrantly enhance ERalpha-mediated signaling axis and play a role in breast cancer development and/or progression. (PMID:18518979)
• Data show that Trio, Ect2, and Vav3 are expressed at higher levels in glioblastoma versus low-grade glioma, and are involved in tumor cell migration and invasion. (PMID:19008376)
• Proteins beta3 integrin, Vav3, Plekhm1, and Src, implicated in attachment defects, had normal exon sequences in a new type of osteopetrosis. (PMID:19546854)
• Vav3 may enhance non-genomic AR activity via PI3K-Akt signaling in addition to AR transcriptional activity, showing that it may have a role in androgen-independent growth in prostate cancer (PMID:20126983)
• Data strongly suggest that VAV2 and VAV3 genes are susceptibility loci in Japanese primary open-angle glaucoma. (PMID:20140222)
• present data indicate a lack of involvement of variations in NTF4, VAV2, and VAV3 with glaucoma pathogenesis in an Indian population. (PMID:20463313)
• These data revealed that Vav3 overexpression as an additional underlying mechanism contributes to elevated sPLA2-IIa expression in prostate cancer (PMID:21455584)
• Data show the importance of Vav3 in castration-resistant prostate cancer (CRPC) and define a nuclear function of Vav3 in regulating androgen receptor (AR) activity. (PMID:21765461)
• VAV3 can be seen as novel candidate gene for schizophrenia in which both rare and common variants may be related to increased genetic risk in a Japanese population. rs1410403 might affect the volume of the left temporal gyri. (PMID:22416266)
• Novel associations for hypothyroidism and autoimmune risk loci include SNPs near the VAV3 gene. (PMID:22493691)
• Study suggests that overexpression of guanine nucleotide exchange factor Vav3 can be a useful marker for predicting the outcome of patients with gastric cancer and that Vav3 targeting can represent a potential modality for treating gastric cancer. (PMID:22544459)
• Among patients with stage IIB or earlier prostate cancer, higher Vav3 expression correlated with lower cumulative biochemical failure-free survival, suggesting that Vav3 may represent a prognostic marker for posttreatment recurrence of prostate cancer. (PMID:22659453)
• These data, which demonstrate physical and functional interactions between Vav3 and an AR splice variant, provide insights into the mechanisms by which Vav3 exploits and enhances AR signaling in the progression to castration-resistant prostate cancer. (PMID:23023561)
• Studies indicate relevance of P-Rex1 and P-Rex2a, in breast tumorigenesis, and suggest that the exchange factors Vav2 and Vav3 play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and metastasis. (PMID:23033535)
• Data indicate that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. (PMID:23033540)
• analysis of a novel interaction between the co-chaperone Cdc37 and Rho GTPase exchange factor Vav3 promotes androgen receptor activity and prostate cancer growth (PMID:23281476)
• Two variants of VAV2 and VAV3, rs2156323 and rs2801219, respectively, were identified in Japanese patients with primary open angle glaucoma, normal tension glaucoma, and developmental glaucoma. (PMID:23402756)
• Data indicate that Vav3 oncogene protein plays a crucial role in prostate cancer growth and malignant behavior, and could be a potential therapeutic target. (PMID:23403204)
• Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. (PMID:23566222)
• Vav3 is involved in the proliferation, migration, and invasion of gastric cancer cell as a tumor oncogene (PMID:24072493)
• This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer. (PMID:24886537)
• A new genome-wide significant association between VAV3 and IgA nephropathy. (PMID:25305756)
• Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway. (PMID:25430880)
• VAV3 overexpression is a novel biomarker for poor prognosis and survival in ovarian carcinoma. (PMID:25715123)
• VAV3 overexpression could be a useful marker for predicting the outcomes of CRC patients and that VAV3 targeting represents a potential modality for treating CRC (PMID:25791293)
• discrete and different functions of VAV3.1 in metastasis and tumorigenesis are conceivable. (PMID:25964534)
• Data show although no any significant differences between patient groups and lean subjects of proteins SYT4, BAG3, APOA1, and VAV3, except for VGF protein, there was a trend between the expression of these four genes and their protein levels. (PMID:26337083)
• Vav3 inhibition can suppress cell activity and promote apoptosis by regulating the apoptosis-related genes through the ERK pathway (PMID:26695150)
• Results found that OSR2, VAV3, and PPFIA3 were significantly hypermethylated in gastric cancer (GC) patients offering a good alternative in a simple, promising, and noninvasive detection of GC. (PMID:27143812)
• Our results indicated that individuals carrying the VAV3 rs7528153 TT genotype were at a significantly increased risk of developing Paget’s Disease of Bone (PMID:27172236)
• Vav3 was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and thereby increased the motility and invasiveness of pancreatic ductal adenocarcinoma cells (PMID:27453460)
• Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex. (PMID:27507811)
• this study shows that the anti-tumor effects of astragaloside IV are mediated by the downregulation of Vav3-mediated Rac1/MAPK activation (PMID:27930970)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch73-383g2.1	ENSDARG00000057107
danio_rerio	vav3b	ENSDARG00000075962
danio_rerio	vav3a	ENSDARG00000086623
mus_musculus	Vav3	ENSMUSG00000033721
rattus_norvegicus	Vav3	ENSRNOG00000020485

Paralogs (22): TRIO (ENSG00000038382), MCF2L2 (ENSG00000053524), PLEKHG2 (ENSG00000090924), MCF2 (ENSG00000101977), ARHGEF7 (ENSG00000102606), PLEKHG1 (ENSG00000120278), MCF2L (ENSG00000126217), ARHGEF6 (ENSG00000129675), ARHGEF9 (ENSG00000131089), VAV1 (ENSG00000141968), TIAM2 (ENSG00000146426), KIAA1755 (ENSG00000149633), PLEKHG4B (ENSG00000153404), TIAM1 (ENSG00000156299), KALRN (ENSG00000160145), VAV2 (ENSG00000160293), ARHGEF40 (ENSG00000165801), SPATA13 (ENSG00000182957), SESTD1 (ENSG00000187231), PLEKHN1 (ENSG00000187583), PLEKHG4 (ENSG00000196155), ARHGEF25 (ENSG00000240771)

Protein

Protein identifiers

Guanine nucleotide exchange factor VAV3 — Q9UKW4 (reviewed: Q9UKW4)

All UniProt accessions (4): E9PMJ5, H0YCG7, H0YDG2, Q9UKW4

UniProt curated annotations — full annotation on UniProt →

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. 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.

Subunit / interactions. Interacts with the PH domain of SH2B2. Interacts (via SH2 domains) with the phosphorylated form of EPHA2. Interacts with ROS1; constitutive interaction that mediates VAV3 phosphorylation.

Tissue specificity. Isoform 1 and isoform 3 are widely expressed; both are expressed at very low levels in skeletal muscle. In keratinocytes, isoform 1 is less abundant than isoform 3. Isoform 3 is detected at very low levels, if any, in adrenal gland, bone marrow, spleen, fetal brain and spinal cord; in these tissues, isoform 1 is readily detectable.

Post-translational modifications. Phosphorylated. Phosphorylation can be mediated by ROS1. In osteoclasts, undergoes tyrosine phosphorylation in response to CSF1.

Induction. Down-regulated by EGF and TGF-beta.

Miscellaneous. May be produced by alternative promoter usage.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UKW4-1	1, Alpha	yes
Q9UKW4-2	2, Beta
Q9UKW4-3	3, VAV3.1
Q9UKW4-4	4

RefSeq proteins (2): NP_001073343, NP_006104* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000980	SH2	Domain
IPR001331	GDS_CDC24_CS	Conserved_site
IPR001452	SH3_domain	Domain
IPR001715	CH_dom	Domain
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR003096	SM22_calponin	Family
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR022613	CH_CAMSAP_2	Domain
IPR035734	VAV3_SH3_2	Domain
IPR035881	VAV3_SH2	Domain
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR037832	PH_Vav	Domain
IPR047015	VAV3_SH3_1	Domain
IPR055251	SOS1_NGEF_PH	Domain

Pfam: PF00017, PF00130, PF00621, PF07653, PF11971, PF22697

UniProt features (30 total): helix 8, domain 6, splice variant 4, sequence variant 4, sequence conflict 3, chain 1, turn 1, zinc finger region 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2D86	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKW4-F1	85.40	0.59

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 141

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-193648	NRAGE signals death through JNK
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2424491	DAP12 signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis
R-HSA-9748787	Azathioprine ADME

MSigDB gene sets: 0 (showing top):

GO Biological Process (21): angiogenesis (GO:0001525), immune response-regulating cell surface receptor signaling pathway (GO:0002768), vesicle fusion (GO:0006906), DNA damage response (GO:0006974), integrin-mediated signaling pathway (GO:0007229), small GTPase-mediated signal transduction (GO:0007264), regulation of cell size (GO:0008361), response to xenobiotic stimulus (GO:0009410), cell migration (GO:0016477), lamellipodium assembly (GO:0030032), platelet activation (GO:0030168), neutrophil chemotaxis (GO:0030593), positive regulation of B cell proliferation (GO:0030890), Fc-epsilon receptor signaling pathway (GO:0038095), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), positive regulation of cell adhesion (GO:0045785), B cell receptor signaling pathway (GO:0050853), regulation of small GTPase mediated signal transduction (GO:0051056), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cell projection assembly (GO:0030031), intracellular signal transduction (GO:0035556)

GO Molecular Function (6): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), epidermal growth factor receptor binding (GO:0005154), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): immunological synapse (GO:0001772), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
RHO GTPase cycle	5
Fc epsilon receptor (FCERI) signaling	2
Platelet activation, signaling and aggregation	1
Cell death signalling via NRAGE, NRIF and NADE	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
DAP12 interactions	1
EPH-Ephrin signaling	1
GPCR downstream signalling	1
Signaling by VEGF	1
VEGFA-VEGFR2 Pathway	1
Leishmania phagocytosis	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell surface receptor signaling pathway	2
GTPase regulator activity	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
immune response-regulating signaling pathway	1
vesicle organization	1
vesicle-mediated transport	1
organelle membrane fusion	1
cellular response to stress	1
intracellular signaling cassette	1
regulation of cellular component size	1
response to chemical	1
cell motility	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
cell activation	1
blood coagulation	1
granulocyte chemotaxis	1
neutrophil migration	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of B cell activation	1
Fc receptor signaling pathway	1
Fc receptor mediated stimulatory signaling pathway	1
phagocytosis	1
Fc-gamma receptor signaling pathway	1
cell adhesion	1
regulation of cell adhesion	1
positive regulation of cellular process	1
antigen receptor-mediated signaling pathway	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
cellular component assembly	1
cell projection organization	1
GTP binding	1

Protein interactions and networks

STRING

1472 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VAV3	LCP2	Q13094	994
VAV3	SYK	P43405	969
VAV3	AKT1	P31749	910
VAV3	GRB2	P29354	746
VAV3	SRC	P12931	742
VAV3	CDC42	P21181	725
VAV3	GPSM2	P81274	685
VAV3	RHOG	P35238	671
VAV3	TYROBP	O43914	654
VAV3	RABIF	P47224	649
VAV3	NCK1	P16333	638
VAV3	AKAP13	Q12802	632
VAV3	DAPP1	Q9UN19	630
VAV3	WAS	P42768	620
VAV3	SLC25A24	Q6NUK1	590

IntAct

40 interactions, top by confidence:

A	B	Type	Score
EGFR	SHC1	psi-mi:“MI:0914”(association)	0.980
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
GRB2	VAV3	psi-mi:“MI:0915”(physical association)	0.850
CBLB	VAV3	psi-mi:“MI:0915”(physical association)	0.560
ZRANB1	VAV3	psi-mi:“MI:0915”(physical association)	0.560
RINT1	VAV3	psi-mi:“MI:0915”(physical association)	0.560
GRB2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
VAV3	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	ERBB3	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	AR	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	KIT	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	MET	psi-mi:“MI:0407”(direct interaction)	0.440
VAV3	ESR1	psi-mi:“MI:0915”(physical association)	0.400
VAV3	PIK3R1	psi-mi:“MI:0915”(physical association)	0.400
VAV3	SH3BP2	psi-mi:“MI:0915”(physical association)	0.400
DDR1	INPPL1	psi-mi:“MI:0914”(association)	0.350
DDR1	PIK3R2	psi-mi:“MI:0914”(association)	0.350
DDR1	RASA1	psi-mi:“MI:0914”(association)	0.350
GRB2	MYO1C	psi-mi:“MI:0914”(association)	0.350
VAV3	ALK	psi-mi:“MI:0914”(association)	0.350
VAV3	GRB2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (63): VAV3 (Affinity Capture-MS), VAV3 (Affinity Capture-MS), VAV3 (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), VAV3 (Affinity Capture-Western), VAV3 (Affinity Capture-Western), VAV3 (Affinity Capture-Western), VAV3 (Affinity Capture-MS), VAV3 (Affinity Capture-MS), VAV3 (Two-hybrid), VAV3 (Two-hybrid), RINT1 (Two-hybrid), GRB2 (Two-hybrid), PDGFRB (Affinity Capture-Western), EGFR (Affinity Capture-Western)

ESM2 similar proteins: A4II46, A6QQZ7, A7MBL8, A8KBF6, B4F7E7, D3ZAA9, E2QY99, O00560, O88910, O88954, P15498, P27870, P29074, P31016, P54100, P70175, P78352, Q08DN7, Q12959, Q13368, Q14168, Q15700, Q16513, Q28C55, Q5PYH6, Q5PYH7, Q5RDQ2, Q5T2T1, Q5U2Y3, Q62108, Q62696, Q62936, Q63622, Q6P0D7, Q6R005, Q8AVG0, Q8BPM2, Q8BVD5, Q8BWW9, Q8N3R9

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, A7A261, B0S6J3, B1V8A0, D4A208, F1LM93, F1LXF1, F1RDG9, O35413, O43295, O75044, O94875, P00523, P00525, P05480, P06241, P07947, P09324, P09769, P0DJJ0, P0DMP2, P10936, P11274, P12931, P13115, P13116, P13406, P14084, P14085, P15054, P15882, P19706, P27446, P27447, P30337, P32793, P39688, P42686

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SRC	up-regulates	VAV3	phosphorylation
VAV3	“up-regulates activity”	RHOA	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PI3K events in ERBB2 signaling	6	191.9×	1e-11
Signaling by ERBB2 ECD mutants	6	191.9×	1e-11
Constitutive Signaling by EGFRvIII	5	169.9×	3e-09
GAB1 signalosome	5	151.1×	5e-09
Signaling by ERBB2 KD Mutants	7	141.0×	2e-12
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	135.9×	7e-09
SHC1 events in ERBB2 signaling	5	113.3×	2e-08
Signaling by ERBB2 TMD/JMD mutants	5	113.3×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	7	75.4×	1e-09
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	55.0×	2e-07
insulin receptor signaling pathway	5	48.2×	6e-06
cell surface receptor protein tyrosine kinase signaling pathway	5	37.8×	1e-05
positive regulation of MAPK cascade	6	21.0×	2e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	5	17.0×	3e-04
negative regulation of apoptotic process	7	10.6×	1e-04
intracellular signal transduction	6	9.9×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

166 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

6026 predictions. Top by Δscore:

Variant	Effect	Δscore
1:107574045:AC:A	donor_gain	1.0000
1:107574046:CC:C	donor_gain	1.0000
1:107574088:T:C	donor_gain	1.0000
1:107574199:C:CC	acceptor_gain	1.0000
1:107598527:T:TA	donor_gain	1.0000
1:107602391:GCTTA:G	donor_loss	1.0000
1:107602392:CTTA:C	donor_loss	1.0000
1:107602393:TTACC:T	donor_loss	1.0000
1:107602394:TA:T	donor_loss	1.0000
1:107602395:ACCAT:A	donor_loss	1.0000
1:107602396:C:CG	donor_loss	1.0000
1:107603045:A:AC	donor_gain	1.0000
1:107603046:C:CC	donor_gain	1.0000
1:107617559:ATACT:A	donor_loss	1.0000
1:107617560:TACTT:T	donor_loss	1.0000
1:107617561:ACTT:A	donor_loss	1.0000
1:107617562:CTTAC:C	donor_loss	1.0000
1:107617563:TT:T	donor_loss	1.0000
1:107617564:T:TC	donor_loss	1.0000
1:107617565:A:AC	donor_gain	1.0000
1:107617566:C:CC	donor_gain	1.0000
1:107617566:C:CT	donor_loss	1.0000
1:107617566:CA:C	donor_gain	1.0000
1:107617566:CACA:C	donor_gain	1.0000
1:107617566:CACAT:C	donor_gain	1.0000
1:107617633:C:CA	acceptor_loss	1.0000
1:107617633:C:CC	acceptor_gain	1.0000
1:107617634:T:C	acceptor_loss	1.0000
1:107704954:GCTTA:G	donor_loss	1.0000
1:107704955:CTTAC:C	donor_loss	1.0000

AlphaMissense

5614 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:107573362:A:G	F838S	1.000
1:107574063:C:T	G829E	1.000
1:107574064:C:G	G829R	1.000
1:107574064:C:T	G829R	1.000
1:107574165:G:T	A795D	1.000
1:107574171:G:T	A793D	1.000
1:107596277:A:T	L762Q	1.000
1:107596297:G:C	F755L	1.000
1:107596297:G:T	F755L	1.000
1:107596298:A:G	F755S	1.000
1:107596299:A:G	F755L	1.000
1:107596310:A:G	L751P	1.000
1:107596310:A:T	L751H	1.000
1:107596337:A:G	L742P	1.000
1:107602461:A:T	I719N	1.000
1:107602463:G:C	H718Q	1.000
1:107602463:G:T	H718Q	1.000
1:107602464:T:C	H718R	1.000
1:107602465:G:C	H718D	1.000
1:107603052:G:C	S709R	1.000
1:107603052:G:T	S709R	1.000
1:107603054:T:G	S709R	1.000
1:107603056:A:T	I708N	1.000
1:107603088:C:A	R697S	1.000
1:107603088:C:G	R697S	1.000
1:107603089:C:A	R697M	1.000
1:107603089:C:G	R697T	1.000
1:107603095:A:G	L695P	1.000
1:107603099:A:C	Y694D	1.000
1:107603122:A:G	L686P	1.000

dbSNP variants (sampled 300 via entrez): RS1000001030 (1:107809367 T>C), RS1000002813 (1:107853818 T>C), RS1000017216 (1:107910492 G>T), RS1000018893 (1:107791847 A>G), RS1000022868 (1:107670839 G>A), RS1000045492 (1:107893779 G>T), RS1000048423 (1:107628511 T>C), RS1000068083 (1:107910221 A>G), RS1000075409 (1:107834240 C>T), RS1000092313 (1:107792167 C>T), RS1000093937 (1:107577206 G>A,C), RS1000104991 (1:107664229 A>G), RS1000119337 (1:107881566 G>C), RS1000142606 (1:107947347 C>T), RS1000152776 (1:107761417 G>A,T)

Disease associations

OMIM: gene MIM:605541 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001474_19	Hypothyroidism	8.000000e-10
GCST002007_7	Adverse response to chemotherapy (neutropenia/leucopenia) (cisplatin)	8.000000e-06
GCST002322_18	Asthma and hay fever	7.000000e-07
GCST002417_1	Plasma thyroid-stimulating hormone levels	2.000000e-08
GCST002655_3	IgA nephropathy	8.000000e-07
GCST002655_4	IgA nephropathy	7.000000e-09
GCST002705_1	Hashimoto thyroiditis versus Graves’ disease	4.000000e-08
GCST003469_9	Response to cognitive-behavioural therapy in anxiety disorder	2.000000e-06
GCST003542_99	Night sleep phenotypes	4.000000e-06
GCST003988_9	Hypothyroidism	3.000000e-22
GCST004753_4	Papillary thyroid cancer	7.000000e-08
GCST004798_5	Differentiated thyroid cancer	8.000000e-08
GCST006898_1	Hypothyroidism	3.000000e-14
GCST007932_64	Medication use (thyroid preparations)	9.000000e-45
GCST008103_103	Bipolar disorder	4.000000e-06
GCST008156_14	Hip circumference adjusted for BMI	2.000000e-07
GCST010002_364	Refractive error	7.000000e-15
GCST010571_79	Autoimmune thyroid disease	4.000000e-52
GCST010579_4	Response to antiepileptic mood-stabilizing treatment in bipolar disorder	2.000000e-06
GCST010653_60	Thyroid stimulating hormone levels	2.000000e-43
GCST012105_1	Facial wrinkles (principal components analysis)	1.000000e-08
GCST012322_7	Triglyceride levels x SSRI defined daily dose interaction in schizophrenia or bipolar disorder	4.000000e-07
GCST90002382_8	Eosinophil percentage of white cells	7.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0009933	Thyroid preparation use measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004530	triglyceride measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

78 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, increases expression, decreases expression	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Estradiol	affects cotreatment, decreases expression, increases expression	5
Valproic Acid	increases expression	5
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	4
Arsenic	affects methylation, decreases expression, increases abundance, affects cotreatment	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Tretinoin	increases expression	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
bisphenol A	affects expression, increases methylation	2
Vorinostat	affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Ozone	affects expression, increases abundance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression	2
Cyclosporine	decreases expression	2
Asbestos, Crocidolite	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
TAK-243	increases sumoylation	1
PF-06840003	decreases reaction, increases expression	1
methylmercuric chloride	decreases expression	1
bis(tri-n-butyltin)oxide	increases expression	1
lead acetate	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
tributyltin	increases expression	1
trichostatin A	decreases expression	1
sodium bichromate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2KX	Abcam HeLa VAV3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

11 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery