SIGNAL TRANSDUCTION TO P70 S6 KINASE 1

描述(申请人提供)：多种人类疾病是由于对细胞生长(细胞质量和大小的增加)、增殖、存活和死亡、分化和发育的不适当调节而引起的。磷脂酰肌醇3-激酶(PI3K)是一种通过产生脂质第二信使来调节有丝分裂信号的媒介，在调节这些过程中起着关键作用。事实上，大约30%的人类癌症具有PTEN功能突变，PTEN是PI3K信号的关键抑制因子。哺乳动物的雷帕霉素靶标mTOR整合了有丝分裂和营养信号，其失调导致与结节性硬化症相关的良性肿瘤的形成，mTOR是一种蛋白激酶、支架和p70-S6激酶(S6K1)激活的关键中介和翻译抑制物4E-BPI的抑制因子。S6K1的激活非常复杂，需要多个不同的依赖于PI3K和mTOR的输入。事实上，S6K1是第一个被证明作用于PI3K和mTOR下游的蛋白激酶，并被免疫抑制剂雷帕霉素完全抑制。突显S6K1在肿瘤形成中的重要性的是，癌基因产物DBL、TIAM-1和Akt已被证明有助于其激活。雷帕霉素除了是一种有效的免疫抑制剂外，还可以预防血管成形术后的再狭窄，由于其抗增殖作用，正在作为一种抗癌药物进行临床试验。因此，很明显，了解PI3K/S6K1和mTOR/S6K1通路是如何调节的，并向下游效应分子发出信号来调节细胞的生长和增殖，对于人类疾病来说是非常重要的。 第一个目标是进一步定义S6K1信号复合体的性质。部分重点将放在mTOR如何调控S6K1，但所描述的筛选应该导致所有S6K1相关蛋白的鉴定和特性。 第二个目标将集中在Rheb，一个最近被证明是mTOR的正向调节者的GTPase是如何被调节的，以及它是如何调节mTOR信号到S6K1和4e-BPI的。 这项建议的第三个目标是描述一个新发现的S6K1特异的相互作用因子和靶标SKAR，并确定它如何参与S6K1信号和功能。 最终目标将继续我们对mTOR靶标S6K1和4EBPI/elF4E如何调控细胞生长和细胞周期进程的描述。

DESCRIPTION (provided by applicant): A variety of human diseases result from improper regulation of cell growth (an increase in cell mass and size), proliferation, survival and death, differentiation and development. Phosphatidylinositol 3-kinase (PI3K), a mediator of mitogenic signals via production of lipid second messengers, plays a critical role in regulating these processes. Indeed, approximately 30% of human cancers have loss of function mutations in PTEN, a critical suppressor of PI3K signaling. The mammalian target of rapamycin, mTOR, integrates both mitogenic and nutrient signals, and its disregulation leads to the formation of benign tumors associated with the disease, tuberous sclerosis, mTOR is a protein kinase, a scaffold, and a critical mediator of p70-S6 kinase (S6K1) activation and suppressor of the translational inhibitor, 4E-BPI. Activation of S6K1 is very complex, requiring multiple distinct PI3K- and mTOR-dependent inputs. Indeed, S6K1 was the first protein kinase shown to act downstream of PI3K and mTOR and is completely inhibited by the immunosuppressant drug rapamycin. Underscoring the importance of S6K1 in tumor formation, the oncogene products Dbl, TIAM-1 and Akt have been shown to contribute to its activation. In addition to being a potent immunosuppressant, rapamycin also prevents restenosis after angioplasty and is in clinical trials as an anticancer drug due to its anti-proliferative effects. Thus, it is clear that understanding how the PI3K/S6K1 and mTOR/S6K1 pathways are regulated and signal to downstream effectors to regulate cell growth and proliferation is of significant importance with regards to human disease. The first objective is to define further the nature of the S6K1 signaling complex. Part of the focus will be on how mTOR regulates S6K1, but the screens described should lead to the identification and characterization of all S6Kl-associated proteins. The second objective will focus on how Rheb, a GTPase recently shown to be a positive modulator of mTOR, is regulated and how it regulates mTOR signaling to S6K1, and 4E-BPI. The third objective of this proposal is to characterize a newly identified S6Kl-specific interactor and target, SKAR, and determine how it contributes to S6K1 signaling and function. The final objective will continue our characterization of how the mTOR targets, S6K1 and 4EBPI/ elF4E, regulate cell growth and cell cycle progression.