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|Coordinate||57,303,079 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||vav 1 oncogene|
|Chromosomal Location||57,279,100-57,328,031 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] 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. The encoded protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation. The encoded protein has been identified as the specific binding partner of Nef proteins from HIV-1. Coexpression and binding of these partners initiates profound morphological changes, cytoskeletal rearrangements and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2012]
PHENOTYPE: Homozygous null mutants exhibit defective T cell maturation, interleukin-2 production, and cell cycle progression. Immunoglobulin class switching is also impaired and attributed to defective T cell help. [provided by MGI curators]
|Amino Acid Change||Lysine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000005889] [ENSMUSP00000108491] [ENSMUSP00000126694]|
AA Change: K444*
|Predicted Effect||probably null|
AA Change: K444*
|Predicted Effect||probably null|
AA Change: K420*
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2018-10-25 5:47 PM by Diantha La Vine|
|Record Created||2017-08-18 9:39 AM by Bruce Beutler|
The tardive phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5503, some of which showed an increase in the B to T cell ratio (Figure 1), an increased in the CD4+ to CD8+ T cell ratio (Figure 2), reduced frequencies of B1 cells (Figure 3), T cells (Figure 4), CD4+ T cells (Figure 5), CD8+ T cells (Figure 6), CD8+ T cells in CD3+ T cells (Figure 7), naive CD4 T cells in CD4 T cells (Figure 8), and naive CD8 T cells in CD8 T cells (Figure 9) with concomitant increased frequencies of central memory CD4 T cells in CD4 T cells (Figure 10), central memory CD8 T cells in CD8 T cells (Figure 11), and effector memory CD4 T cells in CD4 T cells (Figure 12). Expression of IgD on peripheral B cells was reduced (Figure 13), but expression of IgM on peripheral B cells was increased (Figure 14). Expression of CD44 on peripheral T cells (Figure 15), CD4+ T cells (Figure 16), and CD8+ T cells (Figure 17) was increased. The T-dependent antibody response to ovalbumin administered with aluminum hydroxide was also diminished (Figure 18).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 99 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Vav1: an A to T transversion at base pair 57,303,079 (v38) on chromosome 17, or base pair 24,001 in the GenBank genomic region NC_000083. The strongest association was found with a recessive model of linkage to the normalized B to T cell ratio, wherein five variant homozygotes departed phenotypically from 18 homozygous reference mice and 24 heterozygous mice with a P value of 3.933 x 10-29 (Figure 19). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed.
The mutation corresponds to residue 1,428 in the mRNA sequence NM_011691 within exon 14 of 27 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of lysine 444 for a premature stop codon (K444*) in the VAV1 protein.
Vav1 has several domains, including a calponin-homology (CH) domain, an acidic (Ac) motif, a DBL homology (DH) domain, a pleckstrin homology (PH) domain, a phorbol-ester/DAG-type zinc finger (alternatively, C1 domain), a proline-rich region, a Src homology 2 (SH2) domain, and two Src homology 3 (SH3) domains [PDB: 3KY9; (1;2); reviewed in (3)]. Vav1 also has two nuclear localization sequences. The functions of the Vav1 domains are detailed, below.
Each of the Vav1 domains has a unique function. The exact function of the CH domain of Vav1 is unknown; however, it is associated with the induction of calcium release putatively by promoting the activation of phospholipase C-γ (PLCγ; see the record for queen) (4). Several proteins interact with the CH domain (Table 1), but it is unknown if any of these proteins promote Vav1-associated calcium release (5;6). The Ac motif contains three regulatory tyrosines: Tyr142, Tyr160, and Tyr174 (in mouse). Tyr174 binds the GTPase interaction pocket of the DH domain to control the guanine exchange factor (GEF) activity of Vav1 towards the Rho family GTPases Rac1, Rac2 (see the record for bingo), Cdc42, and RhoA . Phosphorylation of Tyr174 after receptor stimulation releases it from the binding pocket and alleviates the autoinhibition (2;7). The DH domain of Vav1 facilitates its GEF activity (8). The PH domain interacts with polyphosphoinositides, promoting Vav1 localization to the plasma membrane and regulation of its GEF activity (9;10). The ZF/C1, proline-rich, SH2, and SH3 domains all mediate protein-protein interactions (Table 1) (9). The outcomes of most of the protein-protein interactions are unknown, but many promote Vav1 function in multiple signaling pathways.
Table 1. Vav1 interacting proteins
The tardive mutation results in substitution of lysine 444 for a premature stop codon (K444*) in the VAV1 protein; amino acid 444 is within the PH domain.
Vav1 is only expressed in hematopoietic tissues, including spleen, thymus, lymph nodes, and bone marrow (1;25). Vav1 is typically localized to the cytoplasm, but can translocate to the nucleus to function in transcription (25).
Vav1 expression has also been detected in several human cancers, including neuroblastomas (27), pancreatic ductal adenocarcinoma (28), lung cancer (29), breast cancer (30), ovarian cancer, prostate cancer (31), medulloblastomas (32), and B-CLL (33).
Vav1 is a guanine nucleotide exchange factor (GEF) for Rho family GTPases. Vav1 is essential for hematopoiesis, including T- and B-cell development and activation (34-36). Vav1 also functions in the adhesion, migration, and phagocytosis of mature hematopoietic cells by regulating cytoskeletal rearrangement [reviewed in (37)]. In NK cells, the Vav1 GEF activity is required for activation of NK-associated killing (38). Vav1 has several functions in macrophages, including Rac-dependent complement-mediated phagocytosis (39), cell migration (40), and chemotaxis to CSF-1 (41).
Vav1 functions downstream of several immune receptors, including the T-cell receptor (TCR) (42), B-cell receptor (BCR) (43), natural killer (NK) receptors (44), FcRI (45), cytokine receptors (46), chemokine receptors (47), and integrins (48). The function of Vav1 in TCR and BCR-associated signaling is described in more detail, below.
In T cell receptor-associated signaling, ligand binding promotes the recruitment of the tyrosine kinases Lck (see the record for Lemon) and Fyn to the receptor complex. CD45 dephosphorylates C-terminal inhibitory tyrosine residues on Lck and Fyn, thereby promoting the activation of Lck and Fyn. Once activated, they phosphorylate ITAMS present on the CD3 and ζ chains. Phosphorylation of the ITAM motifs results in recruitment of ZAP-70 and Syk, which trans- and auto-phosphorylate to form binding sites for SH2 domain- and protein tyrosine binding domain-containing proteins. The Syk family kinases phosphorylate LAT and SLP-76. LAT binds to the adaptor proteins growth factor receptor-bound 2 (Grb2), Src homologous and collagen (Shc) and GRB2-related adaptor downstream of Shc (Gads), as well as phosphatidylinositol 3-kinase (PI3K) and PLC-γ1. SLP-76 binds Vav1, Nck (non-catalytic region of tyrosine kinase adaptor protein), IL-2-induced tyrosine kinase (Itk; see the record for itxaro), PLC-γ1, adhesion and degranulation-promoting adaptor protein (ADAP), and hematopoietic progenitor kinase 1 (HPK1) after Syk-mediated SLP-76 phosphorylation. This proximal signaling complex is required for PLC-γ1-dependent pathways including calcium (Ca2+) mobilization and diacylglycerol (DAG)-induced responses, cytoskeleton rearrangements, and integrin activation pathways. In B cell receptor-mediated signaling, the recruitment of Vav1, Nck, and Ras by BLNK to the BCR activates MAP kinase cascades such as JNK, p38 and extracellular signal regulated kinase (ERK). Together, these signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for puff, xander and panr2) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies.
Following BCR ligation, Blk and/or Lyn phosphorylates the ITAMs of the Igα (see the record for crab)/Igβ BCR subunits (49;50). These phosphotyrosines then act as docking sites for the SH2 domains of Syk, resulting in Syk phosphorylation and activation. Syk phosphorylates a number of downstream targets including BLNK, PLCγ2, and protein kinase C β (PKCβ; see the record for Untied). Phosphorylated BLNK also provides docking sites for Btk, as well as PLCγ2, which results in the additional phosphorylation and activation of PLCγ2 by Btk leading to the hydrolysis of phosphatidylinositol-3,4-diphosphate (PIP2) to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (51). The recruitment of Vav1, Nck, and Ras by BLNK to the BCR activates MAP kinase cascades such as JNK, p38 and extracellular signal regulated kinase (ERK) [reviewed in (52)]. Together, these signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for finlay, xander and panr2) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies [reviewed in (53)].
Vav1 is a binding partner of Nef proteins from HIV-1 (54). Binding of VAV1 and Nef results in morphological changes, cytoskeletal rearrangements, and activation of the JNK/SAPK signaling cascade, subsequently leading to increased viral transcription and replication.
Vav1 putatively functions in malignancies, including neuroblastoma, melanoma, pancreatic tumors and B-cell chronic lymphocytic leukemia. Patients with Vav1-positive tumors had a worse prognosis than patients with Vav1-negative tumors (28). High amounts of nuclear Vav1 in early invasive breast tumors were positively correlated with a low incidence of relapse (31). The link between Vav1 and cancer is unclear, but it has been attributed to its GEF activity towards Rho/RacGTPases, which regulate cytoskeleton organization, gene transcription, cell proliferation, migration, growth, and survival (55;56). Additional links between Vav1 and cancer include Vav1-stimulated MAPK signaling, Vav1-regulated growth factor (e.g., CSF-1) expression (57), Vav1-associated cell cycle progression and gene transcription, Vav1-associated synergistic signaling cross-talk between cancer cells and the tumor microenvironment (58), and Vav1-stimulated autocrine ligand secretion (59).
In the nucleus, Vav1 interacts with components of the DNA-dependent protein kinase complex and with hnRNP proteins as part of transcriptionally active complexes (60-62).
Vav1-deficient (Vav1-/-) mice exhibited embryonic lethality between embryonic day (E) 3.5 and E7.5 (63). A second Vav1-/- mouse model was viable, and exhibited impaired negative T cell selection (64). Single-positive (namely CD4+ T cells), double-positive, and double-negative T cell numbers as well as the number of mature B cells and B1 cells were reduced in the Vav1-/- mice (65-70). T cells from the Vav1-/- mice showed reduced proliferative responses to anti-CD3 stimulation as well as reduced T cell receptor-induced calcium fluxes (64;66;67). The T-dependent IgG response to VSV infection and to NIP-OVA was reduced (70). Homozygous mice expressing an ENU-induced Vav1 allele (F203S) exhibited increased numbers of T cells after immunization (MGI; accessed September 14, 2017).
tardive(F):5'- GGTTAAGGTTAGGATGCGAACC -3'
tardive(R):5'- AGGCTGTCTAGACCATCCAAAC -3'
tardive_seq(F):5'- GTTAGGATGCGAACCCACAGC -3'
tardive_seq(R):5'- GAGGTTGCCTCTGAACTCTAAC -3'
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28. Fernandez-Zapico, M. E., Gonzalez-Paz, N. C., Weiss, E., Savoy, D. N., Molina, J. R., Fonseca, R., Smyrk, T. C., Chari, S. T., Urrutia, R., and Billadeau, D. D. (2005) Ectopic Expression of VAV1 Reveals an Unexpected Role in Pancreatic Cancer Tumorigenesis. Cancer Cell. 7, 39-49.
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30. Sebban, S., Farago, M., Gashai, D., Ilan, L., Pikarsky, E., Ben-Porath, I., and Katzav, S. (2013) Vav1 Fine Tunes p53 Control of Apoptosis Versus Proliferation in Breast Cancer. PLoS One. 8, e54321.
31. Grassilli, S., Brugnoli, F., Lattanzio, R., Rossi, C., Perracchio, L., Mottolese, M., Marchisio, M., Palomba, M., Nika, E., Natali, P. G., Piantelli, M., Capitani, S., and Bertagnolo, V. (2014) High Nuclear Level of Vav1 is a Positive Prognostic Factor in Early Invasive Breast Tumors: A Role in Modulating Genes Related to the Efficiency of Metastatic Process. Oncotarget. 5, 4320-4336.
32. Lindsey, J. C., Kawauchi, D., Schwalbe, E. C., Solecki, D. J., Selby, M. P., McKinnon, P. J., Olson, J. M., Hayden, J. T., Grundy, R. G., Ellison, D. W., Williamson, D., Bailey, S., Roussel, M. F., and Clifford, S. C. (2015) Cross-Species Epigenetics Identifies a Critical Role for VAV1 in SHH Subgroup Medulloblastoma Maintenance. Oncogene. 34, 4746-4757.
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56. Bouzahzah, B., Albanese, C., Ahmed, F., Pixley, F., Lisanti, M. P., Segall, J. D., Condeelis, J., Joyce, D., Minden, A., Der, C. J., Chan, A., Symons, M., and Pestell, R. G. (2001) Rho Family GTPases Regulate Mammary Epithelium Cell Growth and Metastasis through Distinguishable Pathways. Mol Med. 7, 816-830.
57. Sebban, S., Farago, M., Rabinovich, S., Lazer, G., Idelchuck, Y., Ilan, L., Pikarsky, E., and Katzav, S. (2014) Vav1 Promotes Lung Cancer Growth by Instigating Tumor-Microenvironment Cross-Talk Via Growth Factor Secretion. Oncotarget. 5, 9214-9226.
58. Garcia, J. L., Couceiro, J., Gomez-Moreta, J. A., Gonzalez Valero, J. M., Briz, A. S., Sauzeau, V., Lumbreras, E., Delgado, M., Robledo, C., Almunia, M. L., Bustelo, X. R., and Hernandez, J. M. (2012) Expression of VAV1 in the Tumour Microenvironment of Glioblastoma Multiforme. J Neurooncol. 110, 69-77.
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|Science Writers||Anne Murray|
|Authors||Xue Zhong, Jin Huk Choi, and Bruce Beutler|
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