An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity
An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity
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DOI：
10.1093/emboj/19.4.623
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发表时间：
2000-02-15
期刊：
影响因子：
11.4
通讯作者：
Feig, LA
中科院分区：
文献类型：
--
作者：
Goi, T;Shipitsin, M;Feig, LA
c-Src是一种膜相关酪氨酸激酶，可被多种细胞外信号激活，并可调节多种细胞蛋白底物的功能。我们证明，表皮生长因子（EGF）和P-肾上腺素能受体激活c-Src的不同机制，导致不同的c-Src底物的磷酸化。特别是，我们发现EGF受体，而不是β（2）-肾上腺素能受体，激活c-Src的Ral-GTdR依赖性机制。此外，c-Src激活EGF治疗或表达的组成性激活的Ral-GTdR导致酪氨酸磷酸化的Stat 3和corpine，但不Shc或随后的Erk激活。与此相反，c-Src激活异丙肾上腺素导致酪氨酸磷酸化的Shc和随后的Erk激活，但不是酪氨酸磷酸化的corpine或Stat 3。这些结果确定了Ral-GTP酶在EGF受体激活c-Src中的作用，以及EGF通过Stat 3与转录偶联，以及通过coronin与肌动蛋白细胞骨架偶联。它们还表明，c-Src激酶活性可以通过单独的细胞外刺激不同地使用，可能有助于它们产生独特的细胞反应的能力。
c-Src is a membrane-associated tyrosine kinase that can be activated by many types of extracellular signals, and can regulate the function of a variety of cellular protein substrates. We demonstrate that epidermal growth factor (EGF) and P-adrenergic receptors activate c-Src by different mechanisms leading to the phosphorylation of distinct sets of c-Src substrates. In particular, we found that EGF receptors, but not beta(2)-adrenergic receptors, activated c-Src by a Ral-GTPase-dependent mechanism. Also, c-Src activated by EGF treatment or expression of constitutively activated Ral-GTPase led to tyrosine phosphorylation of Stat3 and cortactin, but not Shc or subsequent Erk activation. In contrast, c-Src activated by isoproterenol led to tyrosine phosphorylation of Shc and subsequent Erk activation, but not tyrosine phosphorylation of cortactin or Stat3. These results identify a role for Ral-GTPases in the activation of c-Src by EGF receptors and the coupling of EGF to transcription through Stat3 and the actin cytoskeleton through cortactin, They also show that c-Src kinase activity can be used differently by individual extracellular stimuli, possibly contributing to their ability to generate unique cellular responses.