Vav family proteins couple to diverse cell surface receptors
Vav family proteins couple to diverse cell surface receptors
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DOI：
10.1128/mcb.20.17.6364-6373.2000
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Swat, W
中科院分区：
文献类型：
--
作者：
Moores, SL;Selfors, LM;Swat, W
Vav蛋白是Rho家族GTP酶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蛋白含有几个蛋白质结合结构域，其可以将细胞表面受体连接到下游信号蛋白。Vav 1仅在造血细胞中表达，并响应于多种细胞表面受体的激活而酪氨酸磷酸化。然而，不知道最近鉴定的广泛表达的同种型Vav 2和Vav 3是否可以与类似类别的受体偶联，也不知道所有Vav同种型是否具有相同的功能活性。我们表达Vav 1，Vav 2和Vav 3在同等水平直接比较的反应的Vav蛋白受体激活。虽然每个Vav亚型酪氨酸磷酸化后的代表性受体酪氨酸激酶，整联蛋白和淋巴细胞抗原受体的激活，我们发现独特的方面Vav蛋白偶联在每个受体途径。每个Vav蛋白与活化的表皮生长因子和血小板衍生生长因子（PDGF）受体共沉淀，并且PDGF受体上的多个磷酸化酪氨酸残基能够介导Vav 2酪氨酸磷酸化。在非造血细胞中未检测到整合素诱导的Vav蛋白的酪氨酸磷酸化，除非蛋白酪氨酸激酶Syk也表达，提示Vav蛋白的整联蛋白活化可能限于表达特定酪氨酸激酶的细胞类型。此外，我们发现Vav 1，而不是Vav 2或Vav 3，可以有效地与T细胞受体信号传导合作以增强NFAT依赖性转录，而Vav 1和Vav 3，而不是Vav 2，可以增强NF κ B B依赖性转录。因此，虽然每个Vav亚型可以响应类似的细胞表面受体，但在其下游信号传导途径的激活中存在亚型特异性差异。
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,vith 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 net 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 NF kappa B 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.