Molecular basis of Cell Growth Control by the TOR kinase

TOR，“雷帕霉素的靶标”，是一种巨大的蛋白激酶，其对调节细胞生长响应至关重要。 营养和能量充足，生长因子（如胰岛素和IGF-1）和其他发育 信号.雷帕霉素抑制TOR的一部分作用，这些作用是细胞生长的基础，在某些细胞背景下， 抑制增殖。雷帕霉素由于其免疫抑制作用和抗增殖作用而在临床上使用。 对血管平滑肌细胞的作用;它也正在评估作为抗癌剂。两组近期 这些发现为TOR的功能和调节提供了重要的见解，并得到了该奖项的支持 为这两个领域做出了贡献。生物化学方法证实TOR在两个物理上独立的 多蛋白复合物，其中只有一种（称为TOR复合物1; TORC 1）可被雷帕霉素降解。的 已经阐明了TORC 1通过raptor与其已知底物的相互作用。TOR复合物2抵抗 雷帕霉素，并似乎通过未知的效应物调节肌动蛋白细胞骨架。TORC 2也可以作为 T0 RC 1是Akt所必需的活化激酶（所谓的PDK 2），而T0 RC 1充当Akt的反馈抑制剂。 独立地，胰岛素/IGF-1受体/1型PI-3激酶/Akt和TORC 1之间的分子联系 Rheb是一种Ras样GTdR，Rheb是一种GTdR。 mTOR信号传导至TOR复合物1的正调节因子，其部分直接作用于TORC 1。TSC 1/2是一个 Rheb GT3的激活剂，从而通过Akt抑制Rheb;胰岛素/IGF-1，以及通过Akt的其他输入。 MAPK通路抑制TSC GAP功能，从而促进TORC 1信号传导。氨基酸的消耗， 特别是亮氨酸，抑制TORC 1信号传导，主要独立于TSC 1/2，但以一种被 过量表达的Rheb.我们发现，亮氨酸撤退破坏了Rheb和TOR之间的相互作用。我们 建议对Rheb进行结构-功能分析，以了解其在TOR 1中的相互作用 控制TORC 1信号传导，并定义亮氨酸充足控制Rheb的生化机制。 体内mTOR相互作用。我们将描述对Rheb-GTP、TORC 1和TORC 2的转录反应 并鉴定和表征另外的候选Rheb效应子。此外，我们亦会阐释 TORC 2，通过定义TORC 2特有的组件之间的物理和功能交互， 体内控制TORC 2信号传导的调节输入，以及另外的TORC 2靶标/底物的身份。 这些研究的结果将为这一途径的治疗干预提供依据，这对两者都至关重要。 人类癌症和2型糖尿病等疾病

TOR, the "target of rapamycin" is a giant protein kinase that is critical to the regulation of cell growth in response to nutrient and energy sufficiency, to growth factors (such as insulin and IGF-1) and to other developmental signals. Rapamycin inhibits a subset of TOR's actions that underlie cell growth, and in some cell backgrounds, inhibits proliferation. Rapamycin is in clinical use because of its immunosuppressant action and antiproliferative effects on vascular smooth muscle cells; it is also under evaluation as an anti-cancer agent. Two sets of recent discoveries have provided important insight into TOR function and regulation, and work supported by this award has contributed to both areas. Biochemical methods established that TOR functions in two physically independent multiprotein complexes, only one of which (called TOR complex 1; TORC1) is inhibitable by Rapamycin. The interaction of TORC1 with its known substrates through raptor has been elucidated. TOR complex 2 is resistant to rapamycin, and appears to regulate the actin cytoskeleton through unknown effectors. TORC2 also serves as a necessary activating kinase (so called PDK2) for Akt, whereas TORC1 acts as a feedback inhibitor of Akt. Independently, the molecular connection between the insulin/IGF-1 receptors/Type 1 PI-3Kinase/Akt and TORC1 was shown to be the Tuberous Sclerosis heterodimer complex (TSC1/2) and Rheb, a Ras-like GTPase, Rheb is a positive regulator of mTOR signaling to TOR complex 1, that acts in part directly on TORC1. TSC1/2 is an activator of Rheb GTPase, thereby inhibiting Rheb; insulin/IGF-1, through Akt,and other inputs through the MAPK pathway suppress TSC GAP function, thereby promoting TORC1 signaling. Depletion of amino acids, especially leucine, inhibits TORC1 signaling, mostly independent of TSC1/2, but in a manner that is rescued by overexpressed Rheb. We find that leucine withdrawal disrupts'the interaction between Rheb and TOR. We propose to carry out a structure-function analysis of Rheb so as to understand how its interactions within TOR1 control TORC1 signaling, and define the biochemical mechanism by which leucine sufficiency controls the Rheb- mTOR interaction in vivo. We will characterize the transcriptional responses to Rheb-GTP, TORC1 and TORC2 and identify and characterize additional candidate Rheb effectors. In addition, we will elucidate the operation of TORC2, by defining the physical and functional interactions among the components unique to TORC2, the regulatory inputs that control TORC2 signaling in vivo, and the identity of additional TORC2 targets/substrates. The results of these studies will provide basis for therapeutic interventions in this pathway, which is crucial to both human cancers and to diseases like Type 2 diabetes