Role of c-Src tyrosine kinase in EGF-induced mitogenesis.
Role of c-Src tyrosine kinase in EGF-induced mitogenesis.
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DOI：
10.2741/a208
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发表时间：
1997-10
期刊：
影响因子：
--
通讯作者：
Belsches Ap;Parsons Sj
中科院分区：
文献类型：
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作者：
Belsches Ap;Parsons Sj
c-Src是细胞质、膜相关、非受体酪氨酸激酶的原型，是从许多酪氨酸激酶多肽生长因子受体发出的促有丝分裂信号的共转导子。此类受体的实例包括结合血小板衍生生长因子（PDGF）、集落刺激因子-1（CSF-1）和表皮生长因子（EGF）的那些。对c-Src促进受体信号传导的机制的研究表明，这两种蛋白质之间的相互作用是双向的，即，c-Src可以结合、磷酸化并激活受体，反之亦然。这些相互作用的结果似乎是增强特定底物的磷酸化。描述哪些细胞蛋白质是酪氨酸激酶的底物，并确定酪氨酸磷酸化对特定底物功能的影响是当前研究的目标。利用小鼠C3 H10 T成纤维细胞模型，研究了一组野生型和突变型c-Src/EGF受体过表达子对EGF的时间和空间第二信使反应，c-Src和EGF受体的底物之间的差异以及酪氨酸磷酸化对底物的影响功能开始显现。在10 T模型中，c-Src的优选底物几乎完全由与肌动蛋白细胞骨架或与粘着斑相关的那些分子组成，例如corneum、p190 RhoGAP和p130 CAS，而EGF受体的优选底物包括受体本身、SHC、磷脂酶C-γ和p62 DOK。虽然主要的促有丝分裂信号通路被认为直接从受体（通过SHC/GRB 2/SOS/Ras/Raf/MEK/MAP激酶/Elk 1）进行，但越来越多的证据表明，参与调节肌动蛋白细胞骨架的蛋白质（如c-Src底物）也参与有丝分裂，作为生长信号的独特转导子和/或作为抗凋亡条件（基质附着）的监测器。如何c-Src可能有助于通过酪氨酸磷酸化的EGF促有丝分裂反应或与其特定的底物进行了讨论。细胞Src（c-Src）是一个细胞内膜相关酪氨酸激酶家族的原型，是多种生长因子受体（包括表皮生长因子（EGF）、血小板衍生生长因子（PDGF）、集落刺激因子-1（CSF-1）和碱性成纤维细胞生长因子（bFGF）的受体）启动的有丝分裂所必需的。C-Src也在许多相同的人类癌中过表达和/或激活，这些癌过表达EGF受体（EGFR）家族的成员，这表明这两种类型的酪氨酸激酶可以在人类肿瘤的发生过程中合作。本文综述了c-Src在EGF依赖的有丝分裂和肿瘤发生中的作用，即，c-Src与受体之间的相互作用，c-Src底物的鉴定，它们的功能，以及酪氨酸磷酸化对其功能的影响。其他促有丝分裂和信号系统的概要也包括比较的目的。
c-Src, the prototype of the cytoplasmic, membrane-associated,non-receptor tyrosine kinases, is a co-transducer of mitogenic signals emanating from a number of tyrosine kinase polypeptide growth factor receptors. Examples of such receptors include those that bind the platelet-derived growth factor (PDGF), colony stimulating factor-1 (CSF-1), and epidermal growth factor (EGF). Investigations into the mechanisms by which c-Src contributes to receptor signaling suggest that interactions between the two proteins are bidirectional, i.e., that c-Src can bind, phosphorylate, and activate the receptor, and vice versa. The consequences of these interactions appear to be enhanced phosphorylation of specific substrates. Delineating which cellular proteins are substrates of which tyrosine kinase and determining the consequences of tyrosine phosphorylation on the function of specific substrates are the goals of current investigations. Utilizing the murine C3H10T fibroblast model, in which a panel of wild type and mutant c-Src/EGF receptor overexpressors has been studied for temporal and spatial second messenger responses to EGF, distinctions between substrates of c-Src and the EGF receptor and the effects of tyrosine phosphorylation on substrate function are beginning to emerge. In the 10T model, preferred substrates of c-Src are almost exclusively comprised of those molecules that associate with the actin cytoskeleton or with focal adhesions, such as cortactin, p190RhoGAP, and p130CAS, while preferred substrates of the EGF receptor include the receptor itself, SHC, phospholipase C-gamma and p62DOK. While the major mitogenic signaling pathway is thought to proceed directly from the receptor (through SHC/GRB2/SOS/Ras/Raf/MEK/MAPkinase/Elk1), more evidence is accumulating to suggest that proteins involved in regulating the actin cytoskeleton (such as c-Src substrates) also participate in mitogenesis, either as unique transducers of growth signals and/or as monitors of anti-apoptotic conditions (substratum attachment). How c-Src may contribute to the EGF mitogenic response through tyrosine phosphorylation of or association with its specific substrates is discussed. Cellular Src (c-Src), prototype for a family of intracellular membrane-associated tyrosine kinases, is required for mitogenesis initiated by multiple growth factor receptors, including the receptors for epidermal growth factor (EGF), platelet-derived growth factor (PDGF), colony stimulating factor-1 (CSF-1), and the basic fibroblast growth factor (bFGF). C-Src is also overexpressed and/or activated in many of the same human carcinomas that overexpress members of the EGF receptor (EGFR) family, suggesting that the two types of tyrosine kinases can cooperate during the genesis of human tumors. This review focuses on the role of c-Src in EGF-dependent mitogenesis and tumorigenesis, i.e., on the interactions between c-Src and the receptor and on identification of c-Src substrates, their functions, and the effects of tyrosine phosphorylations on their functions. A synopsis of other mitogenic and signaling systems is also included for comparative purposes.