The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling
The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling
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DOI：
10.1074/jbc.m313955200
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发表时间：
2004-07-09
影响因子：
4.8
通讯作者：
Bennett, AM
中科院分区：
文献类型：
--
作者：
Kolli, S;Zito, CI;Bennett, AM
Src同源2（SH 2）结构域的酪氨酸磷酸酶，SHP-2的催化活性，是必需的几乎所有的信号转导作用。因此，阐明SHP-2信号传导的分子机制取决于其靶底物的鉴定。在这份报告中，我们已经使用SHP-2底物捕获突变体，以确定作为一个假定的SHP-2底物的主要穹窿蛋白（MVP）。MVP是功能未知的细胞质核糖核蛋白复合物拱顶的主要成分。我们发现MVP在体外被SHP-2去磷酸化，在体内与SHP-2形成酶-底物复合物。响应于表皮生长因子（EGF），SHP-2通过其SH 2结构域与酪氨酰磷酸化MVP缔合。MVP还与细胞外调节激酶（Erks）的活化形式相互作用，以响应EGF，并在MCF-7乳腺癌细胞中检测到酪氨酸磷酸化MVP，SHP-2和Erks之间的组成型复合物。使用MVP缺陷的成纤维细胞，我们证明MVP与Ras合作，以获得最佳EGF诱导的Elk-1激活，并且是细胞存活所需的。我们提出MVP作为SHP-2和Erk的新型支架蛋白发挥作用。SHP-2对MVP酪氨酰磷酸化的调节可能在细胞存活信号中起重要作用。
The catalytic activity of the Src homology 2 (SH2) domain-containing tyrosine phosphatase, SHP-2, is required for virtually all of its signaling effects. Elucidating the molecular mechanisms of SHP-2 signaling, therefore, rests upon the identification of its target substrates. In this report, we have used SHP-2 substrate-trapping mutants to identify the major vault protein (MVP) as a putative SHP-2 substrate. MVP is the predominant component of vaults that are cytoplasmic ribonucleoprotein complexes of unknown function. We show that MVP is dephosphorylated by SHP-2 in vitro and it forms an enzyme-substrate complex with SHP-2 in vivo. In response to epidermal growth factor (EGF), SHP-2 associates via its SH2 domains with tyrosyl-phosphorylated MVP. MVP also interacts with the activated form of the extracellular-regulated kinases (Erks) in response to EGF and a constitutive complex between tyrosyl-phosphorylated MVP, SHP-2, and the Erks was detected in MCF-7 breast cancer cells. Using MVP-deficient fibroblasts, we demonstrate that MVP cooperates with Ras for optimal EGF-induced Elk-1 activation and is required for cell survival. We propose that MVP functions as a novel scaffold protein for both SHP-2 and Erk. The regulation of MVP tyrosyl phosphorylation by SHP-2 may play an important role in cell survival signaling.