Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor

Fischer, Klaus–Dieter; Kong, Young Yun; Nishina, Hiroshi; Tedford, Kerry; Marengere, L. E. M.; Kozieradzki, I.; Sasaki, Takehiko; Starr, Mark D.; Chan, Gabriel; Gardener, S.; Nghiem, Mai; Bouchard, Dennis; Barbacid, Mariano; Bernstein, Alan; Penninger, Josef

doi:10.1016/s0960-9822(98)70224-6

Cited by 395 publications

(386 citation statements)

References 47 publications

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“…Notably, we find that accumulation of the TCR and CD8 as well as phosphotyrosine-containing proteins at the IS is unaffected by the Vav1 mutation. This result appears to contradict earlier reports that Vav1 is required for antibody-induced TCR clustering [10,13]. However, this could be due to the difference between stimulation by antibody versus peptide-MHC complexes.…”

Section: Discussioncontrasting

confidence: 93%

“…3A). This result agrees with the observation that TCR-induced activation of receptor-proximal Src-and Syk-family kinases is normal in Vav1-deficient T cells and thymocytes, as is tyrosine phosphorylation of many cellular proteins [10,11,14].…”

Section: Vav1 Is Not Required For the Assembly Of An Issupporting

confidence: 91%

“…Mice deficient in Vav1 show defective positive and negative selection of thymocytes, consistent with TCR signaling deficits [6,7]. Furthermore Vav1-deficient T cells are defective in TCR-induced proliferation and cytokine synthesis [8][9][10][11]. Analysis of biochemical signaling pathways has shown that in the absence of Vav1, TCR-induced calcium flux, as well as ERK, NF-‹ B and phosphoinositide 3-OH kinase activation are reduced [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 85%

“…Furthermore Vav1-deficient T cells are defective in TCR-induced proliferation and cytokine synthesis [8][9][10][11]. Analysis of biochemical signaling pathways has shown that in the absence of Vav1, TCR-induced calcium flux, as well as ERK, NF-‹ B and phosphoinositide 3-OH kinase activation are reduced [10][11][12][13][14]. Vav1 is a guanine nucleotide exchange factor for members of the Rho-family of GTPases, in particular Rac1, Rac2, RhoG and possibly Cdc42, and its activity is regulated by tyrosine phosphorylation [5].…”

Section: Introductionmentioning

confidence: 99%

“…In view of the well established role for Rhofamily proteins in the regulation of the actin cytoskeleton, it has been proposed that Vav1 may transduce TCR signals to the rearrangement of the actin cytoskeleton. Indeed Vav1-deficient T cells were shown to be defective in TCR-induced actin polymerization [10,13].…”

Section: Introductionmentioning

confidence: 99%

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Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

et al. 2003

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Activation of T lineage cells through the TCR by peptide-MHC complexes on APC is critically dependent on rearrangement of the actin cytoskeleton. Vav1 is a guanine nucleotide exchange factor for members of the Rho/Rac family of GTPases which is activated following TCR stimulation, suggesting that it may transduce TCR signals to the activation of some or all actin-controlled processes. We show that Vav1-deficient double-positive thymocytes are less efficient at forming conjugates with APC presenting agonist peptide than wild-type cells are. Furthermore we demonstrate that Vav1 is required for TCR-induced activation of the integrin LFA-1, which is likely to explain the defect in conjugate formation. However, once Vav1-deficient cells form a conjugate, the assembly of proteins into an immunological synapse at the conjugate interface is normal. In contrast, thymocyte polarization is defective in the absence of Vav1, as judged by the relocalization of the microtubule-organizing center. These data demonstrate that Vav1 transduces signals to only a subset of cytoskeletondependent events at the immunological synapse.

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Section: Discussioncontrasting

confidence: 93%

Section: Vav1 Is Not Required For the Assembly Of An Issupporting

confidence: 91%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

et al. 2003

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Defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help

et al. 1999

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Vav, a guanine nucleotide exchange factor for members of the Rho family of small GTPases, is activated through engagement of B and T lymphocyte antigen receptors. It is important for establishing the signaling threshold of the TCR, as mice lacking Vav display defective thymo-cyte selection. Here, conventional B cells are shown to develop normally in Vav-deficient mice but these mice have few B-1 B cells. The threshold for inducing B cell proliferation through BCR engagement in vitro is greater in Vav-deficient B cells. Nevertheless, in vivo the mutant mice have normal antibody responses to haptenated Ficoll. In contrast, Vav −/− mice show defective class switching to IgG and germinal center formation when immunized with haptenated protein. Interestingly, this defect is reversed in chimeras where normal T cells are present. Antigen-specific proliferation of T cells in the T zone was found to be similar in wild-type and Vav −/− mice but the induction of IL-4 mRNA and switch transcripts was specifically impaired. These results suggest that defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help.

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The oncogene product Vav is a crucial regulator of primary cytotoxic T cell responses but has no apparent role in CD28-mediated co-stimulation

et al. 1999

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The guanine nucleotide-exchange factor Vav is a regulator of antigen-mediated cytoskeletal reorganization required for receptor clustering, proliferation and thymic selection. Moreover, Vav has been identified as a major substrate in the CD28 signal transduction pathway and overexpression of Vav enhances TCR-mediated IL-2 secretion in T cells. Here we show that CD3-plus CD28-mediated proliferation and IL-2 production were reduced in vav gene-deficient T cells. However, Vav had no apparent role in phorbol 12-myristate 13-acetate-plus CD28-mediated proliferation and IL-2 production, suggesting that Vav acts downstream of the TCR/CD3 complex. In vivo, Vav expression was crucial to generate primary vesicular stomatitis virus (VSV)-specific cytotoxic T cell responses. In contrast, vav −/− mice exhibited a reduced but significant footpad swelling after lymphocytic choriomeningitis virus (LCMV) infections and mounted a measurable primary cytotoxic T cell response to LCMV. Upon in vitro restimulation, cytotoxic T cell responses of both VSV-and LCMV-infected mice reached near normal levels. Our data provide the first genetic evidence that Vav is an important effector molecule that relays antigen receptor signaling to IL-2 production and activation of cytotoxic T cells.

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Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor

Abstract: Vav is a crucial regulator of TCR-mediated Ca2+ flux, cytoskeletal reorganization and TCR clustering, and these are required for T-cell maturation, interleukin-2 production and cell cycle progression.

Cited by 395 publications

References 47 publications

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

Vav1 transduces TCR signals required for LFA‐1 function and cell polarization at the immunological synapse

Defective immunoglobulin class switching in Vav-deficient mice is attributable to compromised T cell help

The oncogene product Vav is a crucial regulator of primary cytotoxic T cell responses but has no apparent role in CD28-mediated co-stimulation

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