Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

Reynolds, Lucinda F.; Smyth, Lesley A.; Norton, Trisha; Freshney, Norman W.; Downward, Julian; Kioussis, Dimitris; Tybulewicz, Victor L. J.

doi:10.1084/jem.20011663

Cited by 205 publications

(247 citation statements)

References 58 publications

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“…Furthermore, up-regulation of the activation marker CD69 in response to peptide was similarly impaired in Vav1 -/-cells (not shown). This was consistent with previous observations that mutation of Vav1 reduces a number of TCR signaling pathways in thymocytes but does not completely abrogate them [6,14].…”

Section: Reduced Sensitivity Of Vav1 -/-Thymocytes To Tcr Stimulationsupporting

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%

“…Firstly, we and others have shown that Vav1 transduces signals to the activation of PLC + 1 and thus to an intracellular calcium flux [6,10,11,13,14]. This flux in turn activates the calcium-dependent protease caspian, which is required for LFA-1 clustering [28].…”

Section: Discussionmentioning

confidence: 94%

“…In the resultant F5, Rag1 -/-, g 2m -/-mice, the absence of class I molecules causes a complete block in positive selection and thus all the F5-TCR-expressing thymocytes are blocked at the DP stage. To investigate the function of Vav1 within these cells we bred the Vav1 mutation onto this background, generating Vav1 -/-, F5, Rag1 -/-, g 2m -/-mice [14]. As expected, thymic development in these mice was also completely arrested at the DP stage, and Vav1 +/+ and Vav1 -/-DP thymocytes expressed equal levels of TCR, CD3, CD4 and CD8 [14].…”

Section: Reduced Sensitivity Of Vav1 -/-Thymocytes To Tcr Stimulationmentioning

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%

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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: Reduced Sensitivity Of Vav1 -/-Thymocytes To Tcr Stimulationsupporting

confidence: 93%

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

confidence: 91%

Section: Discussionmentioning

confidence: 94%

Section: Reduced Sensitivity Of Vav1 -/-Thymocytes To Tcr Stimulationmentioning

confidence: 85%

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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Rosmarinic acid inhibits TCR‐induced T cell activation and proliferation in an Lck‐dependent manner

Won¹,

Hur²,

Hur³

et al. 2003

Eur J Immunol

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Lck is a T cell-restricted Src family protein tyrosine kinase that plays pivotal roles in TCRmediated signaling. We aimed to identify novel agents that could disrupt the molecular interaction of the Src homology 2-domain of Lck (Lck SH2) with its binding partners, with the expectation that this would impair TCR signaling and generate immunosuppression. Largescale screening of plant extracts indicated that rosmarinic acid (RosA) in extracts of Prunella vulgaris consistently inhibits the interaction between Lck SH2 and a peptide containing its consensus binding sequence (pYEEI). The inhibitory effect of RosA was specific for SH2 domains of Src family protein tyrosine kinase. RosA inhibited TCR-induced-Ca 2+ mobilization and IL-2 promoter activation but not phorbol 12-myristate 13-acetate/ionomycininduced IL-2 promoter activation, indicating its point of inhibition at the membrane proximal site of TCR signaling. Furthermore, RosA inhibited TCR-induced splenocyte proliferation as well as one-way MLR at an IC 50 of 25-50 ? M and inhibited cytokine expression such as IL-2 and IFN-+ . Here, we first report RosA as an inhibitor of TCR-signaling and subsequent T cell proliferation.

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Commentary Vav‐1 and T cells

Cantrell

2003

Eur J Immunol

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[I 23942]Vav-1 is a protein expressed predominantly in hematopoietic cells. There has been much work on the biochemistry and biology of this protein and finally some clarity as to the role of Vav-1 in immune cells has been achieved. An excellent paper on this topic was recently published by Ardouin et al. [1].The involvement of Vav-1 in lymphocyte transduction was first indicated by biochemistry -it was seen that this protein was tyrosine-phosphorylated in response to antigen-receptor ligation. Vav-1 is also tyrosinephosphorylated, following ligation of the costimulatory molecule CD28, and forms protein complexes with the tyrosine kinase ZAP-70 and the adapter SLP-76 in activated T cells [2]. These are probably important in regulating Vav-1 cellular localization and catalytic activity. Initially, the predicted protein sequence of Vav-1 indicated that this protein was likely to be a transcription factor and hence its tyrosine phosphorylation was heralded as a mechanism to link antigen-receptors to the cell nucleus [3]. This view changed when a revised, correct Vav-1 sequence was published which revealed that Vav-1 is a 95-kDa protein with src-homology (SH) 2 and SH3 domains and a Dbl homology region which is a characteristic marker of guanine nucleotide exchange proteins (GEF) for Rho family GTPases [4]. There was then a brief period when it was suggested that Vav-1 was a GEF for Ras. However, now it is accepted that Vav-1 is not directly involved in Ras regulation but rather targets the Rho family GTPases Rac-1 and Rac-2 [5, 6].If the early predictions of Vav-1 function were confusing, analysis of Vav-1 knockouts then clarified the importance of this protein for lymphocyte biology. Hence, deletion of the Vav-1 gene by homologous recombination resulted in mice with both B and T cell defects [7]. Notably, mice lacking Vav-1 show severe defects in thymocyte development.In early thymocyte progenitors the process of TCR gselection occurs: cells that successfully rearrange their TCR g -locus and express a functional pre-TCR complex proliferate rapidly and undergo further differentiation to express the coreceptors CD4 and CD8. These cells then undergo TCR § -chain rearrangements and upon expression of a mature § g TCR complex are subjected to the processes of positive and negative selection which generate CD4 or CD8 single-positive thymocytes that exit to the periphery. Loss of Vav-1 causes problems in the two key antigen-receptor checkpoints. There is a marked thymocyte hypocellularity in Vav-null mice that is associated with an incomplete differentiation block at the DN3/ pre-TCR checkpoint stage [8]. This block is leaky but the cells that survive do not develop normally; they show inefficient positive and negative selection [9]. These defects mean that Vav-1-null mice have very few mature peripheral T cells. Moreover, the severe defects in thymocyte development caused by loss of Vav-1 must raise the question of whether Vav-1-null mice have any normal peripheral T cells.In this context, peripheral T cells from Vav-1-...

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Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

Cited by 205 publications

References 58 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

Rosmarinic acid inhibits TCR‐induced T cell activation and proliferation in an Lck‐dependent manner

Commentary Vav‐1 and T cells

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