Protein phosphorylation and growth factor function

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控制细胞生长、分化、存活和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（PI 3 K）是生长因子信号通路中的关键组分，在细胞生长和存活中起重要作用。PI 3 K的关键下游效应子是AKT/PKB蛋白激酶。AKT活化需要两个关键残基的磷酸化，T308被PDK 1磷酸化，S473被PDK 2磷酸化。PDK 2的身份仍然难以捉摸，直到最近将TORC 2（TOR复合物2）鉴定为候选PDK 2。最近的研究已经确定，TORC 2在AKT S473的磷酸化中起关键作用，并受到PI 3 K通路的刺激。PI 3 K通路的失调与许多人类疾病相关，例如癌症和肥大性疾病。我们已经确定Sin 1作为一种新的TORC 2复合物的形成和激酶活性所需的组件。本研究的主要目的是研究胰岛素和PI 3 K对TORC 2调控的分子机制。 该提案的具体目标是： 1.确定Sin 1磷酸化在TORC 2调节中的功能意义 2.确定Rictor和mTOR对Sin 1蛋白水平的调节 3.研究胰岛素和PI 3 K激活TORC 2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