Protein phosphorylation and growth factor function

描述(申请人提供)：这个项目的长期目标是阐明蛋白质磷酸化在控制细胞生长、分化、存活和新陈代谢中的功能和调节，以响应各种生长因子，如EGF和胰岛素。磷脂酰肌醇-3激酶(PI3K)是生长因子信号通路中的重要组成部分，在细胞的生长和存活中起着重要作用。PI3K的一个关键下游效应因子是AKT/PKB蛋白激酶。AKT的激活需要两个关键残基的磷酸化：T308被PDK1磷酸化，S473被PDK2磷酸化。直到最近TORC2(TOR复合体2)被确定为候选PDK2之前，PDK2的身份一直难以捉摸。最近的研究表明，TORC2在AKT S473的磷酸化过程中起着关键作用，并受到PI3K途径的刺激。PI3K通路的失调与许多人类疾病有关，如癌症和肥厚性疾病。我们已经确定SIN1是一种新的TORC2组分，它是形成复合体和激活激酶所必需的。本研究的主要目的是研究胰岛素和PI3K调节TORC2的分子机制。 这项建议的具体目标是： 1.确定SIN1磷酸化在TORC2调控中的功能意义 2.确定Rictor和mTOR对SIN1蛋白水平的调节 3.探讨胰岛素和PI3K激活TORC2的机制

DESCRIPTION (provided by applicant): The long-term goals of this project are to elucidate the function and regulation of protein phosphorylation in the control of cell growth, differentiation, survival, and metabolism in response to various growth factors, such as EGF and insulin. Phosphatidylinositol-3 kinase (PI3K) is a critical component in the growth factor signaling pathway and plays an important role in cell growth and survival. A key downstream effector of PI3K is the AKT/PKB protein kinase. AKT activation requires the phosphorylation of two key residues, T308 by PDK1 and S473 by PDK2. The identity of PDK2 has remained elusive until the recent identification of TORC2 (TOR complex 2) as a candidate PDK2. Recent studies have established that TORC2 plays a key role in the phosphorylation of AKT S473 and is stimulated by the PI3K pathway. Dysregulation of the PI3K pathway is associated with many human diseases, such as cancers and hypertrophic disorders. We have identified Sin1 as a novel TORC2 component required for complex formation and kinase activity. The major goal of this proposal is to investigate the molecular mechanism of TORC2 regulation by insulin and PI3K. The specific aims of the proposal are: 1. To determine the functional significance of Sin1 phosphorylation in regulation of TORC2 2. To determine the regulation of Sin1 protein levels by Rictor and mTOR 3. To investigate the mechanisms of TORC2 activation by insulin and PI3K