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Vav Family Proteins Couple to Diverse Cell Surface Receptors

机译：Vav家族蛋白耦合到不同的细胞表面受体

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Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFκB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.
机译：Vav蛋白是Rho家族GTPases的鸟嘌呤核苷酸交换因子，其激活导致肌动蛋白细胞骨架重排和转录改变的途径。 Vav蛋白质包含几个蛋白质结合结构域，可以将细胞表面受体连接到下游信号蛋白。 Vav1专门在造血细胞中表达，酪氨酸磷酸化响应多个细胞表面受体的激活。然而，尚不清楚最近鉴定的广泛表达的同工型Vav2和Vav3是否可以与相似类别的受体偶联，也不知道所有Vav同工型是否具有相同的功能活性。我们以相等的水平表达Vav1，Vav2和Vav3，以直接比较Vav蛋白对受体激活的反应。尽管每个Vav同工型在代表受体酪氨酸激酶，整联蛋白和淋巴细胞抗原受体激活后被酪氨酸磷酸化，但我们在每个受体途径中发现了Vav蛋白偶联的独特方面。与活化的表皮生长因子和血小板衍生的生长因子（PDGF）受体共沉淀的每个Vav蛋白，以及PDGF受体上的多个磷酸化酪氨酸残基均能够介导Vav2酪氨酸磷酸化。除非还表达蛋白质酪氨酸激酶Syk，否则在非造血细胞中未检测到整合素诱导的Vav蛋白质的酪氨酸磷酸化，这表明Vav蛋白质的整合素激活可能仅限于表达特定酪氨酸激酶的细胞类型。此外，我们发现Vav1，而不是Vav2或Vav3，可以有效地与T细胞受体信号传导协同作用，以增强NFAT依赖性转录，而Vav1和Vav3，而不是Vav2，可以增强NFκB依赖性转录。因此，尽管每个Vav同工型都可以响应相似的细胞表面受体，但是它们对下游信号传导途径的激活存在同工型特异性差异。

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