Roccio M, Bos J L, Zwartkruis F J T
Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
Oncogene. 2006 Feb 2;25(5):657-64. doi: 10.1038/sj.onc.1209106.
The mTOR/S6K/4E-BP1 pathway integrates extracellular signals derived from growth factors, and intracellular signals, determined by the availability of nutrients like amino acids and glucose. Activation of this pathway requires inhibition of the tumor suppressor complex TSC1/2. TSC2 is a GTPase-activating protein for the small GTPase Ras homologue enriched in brain (Rheb), GTP loading of which activates mTOR by a yet unidentified mechanism. The level at which this pathway senses the availability of amino acids is unknown but is suggested to be at the level of TSC2. Here, we show that amino-acid depletion completely blocks insulin- and TPA-induced Rheb activation. This indicates that amino-acid sensing occurs upstream of Rheb. Despite this, amino-acid depletion can still inhibit mTOR/S6 kinase signaling in TSC2-/- fibroblasts. Since under these conditions Rheb-GTP levels remain high, a second level of amino-acid sensing exists, affecting mTOR activity in a Rheb-independent fashion.
mTOR/S6K/4E-BP1信号通路整合了源自生长因子的细胞外信号以及由氨基酸和葡萄糖等营养物质的可利用性所决定的细胞内信号。该信号通路的激活需要抑制肿瘤抑制复合物TSC1/2。TSC2是小GTP酶脑富集同源物（Rheb）的GTP酶激活蛋白，Rheb的GTP加载通过一种尚未明确的机制激活mTOR。该信号通路感知氨基酸可利用性的水平尚不清楚，但提示是在TSC2水平。在此，我们表明氨基酸耗竭完全阻断胰岛素和佛波酯诱导的Rheb激活。这表明氨基酸感知发生在Rheb的上游。尽管如此，氨基酸耗竭仍可抑制TSC2基因敲除的成纤维细胞中的mTOR/S6激酶信号传导。由于在这些条件下Rheb-GTP水平仍然很高，因此存在第二层氨基酸感知，以一种不依赖Rheb的方式影响mTOR活性。
