Rapamycin induces transactivation of the EGFR and increases cell survival.
Rapamycin induces transactivation of the EGFR and increases cell survival.
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DOI：
10.1038/onc.2008.490
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发表时间：
2009-03-05
期刊：
影响因子：
8
通讯作者：
Patel, T. B.
中科院分区：
文献类型：
--
作者：
Chaturvedi, D.;Gao, X.;Cohen, M. S.;Taunton, J.;Patel, T. B.
哺乳动物雷帕霉素靶蛋白（mTOR）信号传导网络调节细胞生长、增殖和细胞存活。该途径的失调激活是多种人类疾病如癌症、心脏肥大、血管再狭窄和肾病肥大中的常见事件。尽管mTOR抑制剂雷帕霉素已被广泛用于抑制由于mTOR激活而引起的异常信号传导，该异常信号传导在过度增殖性疾病中起主要作用，但在某些情况下雷帕霉素不减弱细胞增殖和存活。因此，我们研究了细胞可能赋予雷帕霉素抗性的机制。我们的数据显示，在多种细胞类型中，mTOR抑制剂雷帕霉素激活Erk 1/2信号传导。雷帕霉素介导的Erk 1/2信号传导的激活需要（a）表皮生长因子受体（EGFR），（B）其酪氨酸激酶活性，和（c）受体上完整的自磷酸化位点。雷帕霉素处理增加EGFR的酪氨酸磷酸化而不添加生长因子，并且这种受体的反式激活涉及c-Src的激活。我们还表明，雷帕霉素治疗触发激活细胞生存信号通路激活促生存激酶Erk 1/2和p90 RSK。这些研究提供了一种新的范例，通过该范例，细胞逃避抑制mTOR通路的雷帕霉素及其衍生物的凋亡作用。
The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis, and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data shows that in a variety of cell types the mTOR inhibitor rapamycin activates Erk1/2 signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity, and (c) intact auto-phosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the pro-survival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway.
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DOI：
10.1083/jcb.200403069
发表时间：
2004-07-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrington LS;Findlay GM;Gray A;Tolkacheva T;Wigfield S;Rebholz H;Barnett J;Leslie NR;Cheng S;Shepherd PR;Gout I;Downes CP;Lamb RF
通讯作者：
Lamb RF
影响因子：
56.9
作者：
Cohen, MS;Zhang, C;Taunton, J
通讯作者：
Taunton, J
影响因子：
4.8
作者：
Arteaga, CL;Ramsey, TT;Guyer, CA
通讯作者：
Guyer, CA
影响因子：
11.4
作者：
Gschwind, A;Hart, S;Ullrich, A
通讯作者：
Ullrich, A
影响因子：
4
作者：
Huang, S;Houghton, PJ
通讯作者：
Houghton, PJ