Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies
Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies
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DOI：
10.1016/j.cub.2004.08.026
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发表时间：
2004-09-21
期刊：
影响因子：
9.2
通讯作者：
Hunter, T
中科院分区：
文献类型：
--
作者：
Shah, OJ;Wang, ZY;Hunter, T
结节性硬化症是一种主要的良性肿瘤综合征，源于编码肿瘤抑制产物TSC1或TSC2的基因的体细胞损伤。作为Rheb间隙的TSC1-TSC2复合体的功能丧失，从由Rheb、mTOR和S61K组成的细胞生长机制产生结构性的、不受限制的信号。我们在此证明，Rheb/mTOR/S61K盒的结构性激活，无论是通过TSC1或TSC2的基因缺失还是通过Rheb的异位表达，都足以诱导胰岛素抵抗。这是胰岛素受体底物IRS1和IRS2下调的结果，这两种底物限制了从胰岛素受体到PI3K的信号传递。在PI3K下游，存活激酶Akt在TSC1或TSC2缺陷细胞中完全不能被依赖于IRS的生长因子途径如胰岛素或IGF-I激活，但不能被依赖于IRS的途径激活，如PDGF利用的那些途径。在TSC2缺失细胞中，由IGF-1而不是PDGF诱导的抗凋亡程序严重受损。我们的结果表明，Rheb/mTOR/S6K通路的不适当激活施加了一个负反馈程序，以减弱IRS依赖的过程，如细胞存活。
Tuberous sclerosis is a largely benign tumor syndrome derived from the acquisition of somatic lesions in genes encoding the tumor suppressor products, TSC1 or TSC2. Loss of function of the TSC1-TSC2 complex, which acts as a Rheb GAP, yields constitutive, unrestrained signaling from the cell growth machinery comprised of Rheb, mTOR, and S61K. We demonstrate herein that constitutive activation of the Rheb/mTOR/ S61K cassette, whether by genetic deletion of TSC1 or TSC2 or by ectopic expression of Rheb, is sufficient to induce insulin resistance. This is the result of downregulation of the insulin receptor substrates, IRS1 and IRS2, which become limiting for signal transmission from the insulin receptor to PI3K. Downstream of PI3K, the survival kinase, Akt, is completely refractory to activation by IRS-dependent growth factor pathways such as insulin or IGF-I in TSC1- or TSC2-deficient cells but not to activation by IRS-independent pathways such as those utilized by PDGF. The antiapoptotic program induced by IGF-1 but not PDGF is severely compromised in TSC2 null cells. Our results suggest that inappropriate activation of the Rheb/ mTOR/S6K pathway imposes a negative feedback program to attenuate IRS-dependent processes such as cell survival.