Li Yong, Corradetti Michael N, Inoki Ken, Guan Kun-Liang
Department of Biological Chemistry and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Trends Biochem Sci. 2004 Jan;29(1):32-8. doi: 10.1016/j.tibs.2003.11.007.
The tumor-suppressor proteins TSC1 and TSC2 are associated with an autosomal dominant disorder known as tuberous sclerosis complex (TSC). TSC1 and TSC2 function as a heterodimer to inhibit cell growth and proliferation. Another protein, mTOR (mammalian target of rapamycin), is regarded as a central controller of cell growth in response to growth factors, cellular energy and nutrient levels. Recent breakthroughs in TSC research link the TSC1/2 heterodimer protein to the mTOR signaling network. It has recently been shown that TSC2 has GTPase-activating protein (GAP) activity towards the Ras family small GTPase Rheb (Ras homolog enriched in brain), and TSC1/2 antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb. Thus, TSC1/2 and Rheb have pivotal roles in mediating growth factors, nutrient and energy sensing signals to mTOR-dependent targets. These discoveries lend new insight into TSC pathogenesis.
肿瘤抑制蛋白TSC1和TSC2与一种名为结节性硬化症复合体（TSC）的常染色体显性疾病相关。TSC1和TSC2作为异二聚体发挥作用，以抑制细胞生长和增殖。另一种蛋白，雷帕霉素的哺乳动物靶点（mTOR），被视为响应生长因子、细胞能量和营养水平的细胞生长的核心调控因子。TSC研究中的最新突破将TSC1/2异二聚体蛋白与mTOR信号网络联系起来。最近有研究表明，TSC2对Ras家族小GTP酶Rheb（富含于脑中的Ras同源物）具有GTP酶激活蛋白（GAP）活性，并且TSC1/2通过刺激Rheb的GTP水解来拮抗mTOR信号通路。因此，TSC1/2和Rheb在介导生长因子、营养和能量传感信号至mTOR依赖性靶点方面具有关键作用。这些发现为TSC的发病机制提供了新的见解。
