REQUIREMENT FOR INTRINSIC PROTEIN TYROSINE KINASE IN THE IMMEDIATE AND LATE ACTIONS OF THE EGF RECEPTOR
REQUIREMENT FOR INTRINSIC PROTEIN TYROSINE KINASE IN THE IMMEDIATE AND LATE ACTIONS OF THE EGF RECEPTOR
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DOI：
10.1038/328820a0
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发表时间：
1987-08-27
期刊：
影响因子：
64.8
通讯作者：
ROSENFELD, MG
中科院分区：
文献类型：
--
作者：
CHEN, WS;LAZAR, CS;ROSENFELD, MG
表皮生长因子（EGF）受体是一种相对分子质量为170，000的跨膜糖蛋白，具有内在配体依赖性蛋白酪氨酸激酶活性1 -6。EGF与其受体的结合激活了许多直接的生物化学过程，如细胞内游离钙，pH值的改变，以及几个响应基因的转录增加，通常在DNA复制和细胞分裂中达到高潮7 -14。消除三种相关癌基因v-src、v-mos和v-fps的酪氨酸激酶活性，消除了它们转化细胞的能力15 -17。一些报告表明，EGF受体功能的特定方面与内在酪氨酸激酶活性无关18，19;然而，这些研究使用了一种抗EGF受体的抗体，该抗体未能激活外源底物的磷酸化18，并且在EGF受体酪氨酸激酶结构域中插入突变，该突变未显示出消除细胞中的蛋白激酶活性19。由于许多跨膜受体与内在膜蛋白相互作用以激活第二信使系统，因此重要的是要通过实验来解决除了激活内在酪氨酸激酶活性之外的机制是否介导一些EGF作用。从功能分析的EGF受体含有一个单一的氨基酸突变所需的磷酸盐从ATP转移的网站，我们得出结论，EGF受体的酪氨酸激酶活性是必不可少的EGF的各种生化作用，包括细胞内钙的快速改变，基因转录的激活，受体下调和最终的刺激作用对细胞增殖。
The epidermal growth factor (EGF) receptor is a transmembrane glycoprotein of relative molecular mass 170,000 with intrinsic ligand-dependent protein tyrosine kinase activity1–6. Binding of EGF to its receptor activates a number of immediate biochemical processes, such as alterations of intracellular free calcium,pH, and increased transcription of several responsive genes, which usually culminate many hours later in DNA replication and cell division7–14. Abolishing the tyrosine kinase activity of three related oncogenes, v-src, v-mos, and v-fps, eliminates their capacity to transform cells15–17. Several reports have suggested that specific aspects of EGF receptor function are independent of the intrinsic tyrosine kinase activity18,19; however, these studies used an antibody against EGF receptor which failed to activate phosphoryla-tion of exogenous substrates18and an insertional mutation in the EGF receptor tyrosine kinase domain which had not been shown to abolish protein kinase activity in cells19. Because many transmembrane receptors interact with intrinsic membrane proteins to activate second messenger systems, it is important to resolve experimentally whether mechanisms, in addition to activation of the intrinsic tyrosine kinase activity, mediate some EGF actions. From functional analyses of an EGF receptor containing a single amino-acid mutation at a site required for phosphate transfer from ATP, we conclude that the tyrosine kinase activity of the EGF receptor is essential for the diverse biochemical effects of EGF, including rapid alterations in intracellular calcium, activation of gene transcription, receptor down-regulation and the ultimate stimulatory effects on cell proliferation.