Protein phosphorylation and growth factor function

蛋白质磷酸化和生长因子功能

• 批准号: 7892688
• 负责人: Kun-Liang Guan
• 金额: $ 26.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892688
• 关键词: 1-Phosphatidylinositol 3-Kinase; Biological Assay; Cell physiology; Complex; Data; Disease; EGF gene; Goals; Growth Factor; In Vitro; Insulin; Knock-out; Malignant Neoplasms; Mammals; Maps; Metabolism; Molecular; Nutrient; PDPK1 gene; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Raptors; Regulation; Regulation of Cell Size; Role; Signal Pathway; Signal Transduction; Sirolimus; Stress; TSC1/2 gene; Testing; Translations; Yeasts; cell growth; cell growth regulation; domain mapping; human FRAP1 protein; human disease; novel; response

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

描述（由申请人提供）：该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，生存和代谢中的功能和调节，以响应各种生长因子，例如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关键成分，并且在细胞生长和存活中起重要作用。 PI3K的关键下游效应子是AKT/PKB蛋白激酶。 AKT激活需要两个关键残基的磷酸化，PDK1的T308和PDK2的S473磷酸化。 PDK2的身份一直难以捉摸，直到最近将TORC2（Tor Complex 2）鉴定为候选PDK2。最近的研究表明，TORC2在AKT S473的磷酸化中起关键作用，并被PI3K途径刺激。 PI3K途径的失调与许多人类疾病（例如癌症和肥厚性疾病）有关。我们已经将SIN1确定为复杂形成和激酶活性所需的新型TORC2成分。该提案的主要目的是研究胰岛素和PI3K调节TORC2调节的分子机制。 该提案的具体目的是： 1。确定SIN1磷酸化在TORC2调节中的功能意义 2。确定rictor和mTOR对SIN1蛋白水平的调节 3。研究胰岛素和PI3K激活TORC2的机制