Protein phosphorylation and growth factor function

项目描述（由申请人提供）：本项目的长期目标是阐明蛋白磷酸化在各种生长因子（如EGF和胰岛素）的作用下，在控制细胞生长、分化、存活和代谢中的功能和调控。磷脂酰肌醇-3激酶（PI3K）是生长因子信号通路的重要组成部分，在细胞生长和存活中起着重要作用。PI3K的一个关键下游效应物是AKT/PKB蛋白激酶。AKT的激活需要两个关键残基的磷酸化，PDK1磷酸化T308， PDK2磷酸化S473。PDK2的身份一直难以捉摸，直到最近发现TORC2 （TOR复合体2）作为候选PDK2。最近的研究表明，TORC2在AKT S473的磷酸化中起关键作用，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是复杂形成和激酶活性所需的新的TORC2组分。本课题的主要目的是研究胰岛素和PI3K调控TORC2的分子机制。

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