FRAP AND THE RAPAMYCIN SENSITIVE SIGNALING PATHWAY

FRAP 和雷帕霉素敏感信号通路

• 批准号: 2877671
• 负责人: JIE CHEN
• 金额: $ 10万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2877671
• 关键词: binding proteins; biological signal transduction; cell growth regulation; enzyme activity; enzyme substrate; microinjections; molecular cloning; protein kinase; protein structure function; protein tyrosine phosphatase; sirolimus; transcription factor; translation factor; yeast two hybrid system

The effects of mitogens on cell proliferation are mediated by increases in both transcription and translation. Much is known about the signaling pathways that link extracellular signals to the nucleus, but less is known about the precise mechanisms involved in the regulation of protein synthesis. Recent studies by a number of investigators have shown that protein translation is regulated by a signaling pathway that is inhibited by the immunosuppressant, rapamycin. Rapamycin in a complex with its binding protein, FKBP-12, binds to a protein termed FRAP (FKBP12-rapamycin-associated protein). By an unknown mechanism the binding of FKBP12-rapamycin to FRAP interferes with signaling initiated by receptor activation of phosphatidylinositol-3-kinase (PI3K). The most well characterized effects of rapamycin are inhibition of p70S6 kinase (p70S6K), a regulator of translational initiation, and decreased phosphorylation of 4E-BP1, a regulator of initiation factor eIF-4E. FRAP is related in primary amino acid sequence to the family of lipid kinases that includes PI3K, however, it is thought to be a protein kinase. Potential substrates for FRAP are 4E-BP1 and regulators of protein phosphatase activity. This application is aimed at investigating several aspects of FRAP. In Aim I, the function of FRAP will be investigated through the identification of novel substrates. The relationship of these substrates to the regulation of p70S6K and 4E- BP1 will be studied. In Aim II, the role of the domain of FRAP that binds FKBP12-rapamycin will be studied. In Aim III, novel proteins that associate with FRAP in a multi-protein complex will be purified and characterized. In Aim IV, the relationship of FRAP to the regulation of protein phosphatases will be studied. By understanding the detailed biochemical properties of FRAP, fundamental questions of how protein translation is coupled to cell cycle progression will be answered.

有丝分裂原对细胞增殖的影响是通过增加 无论是转录还是翻译。 很多人都知道 将细胞外信号与细胞核联系起来的信号通路， 对调控的精确机制知之甚少 蛋白质的合成。 一些研究人员最近的研究表明， 表明蛋白质翻译受信号通路调节， 被免疫抑制剂雷帕霉素抑制 雷帕霉素 与其结合蛋白FKBP-12的复合物结合称为 FRAP（FKBP 12-雷帕霉素相关蛋白）。 通过一种未知的机制 FKBP 12-雷帕霉素与FRAP的结合干扰了FRAP启动的信号传导 通过磷脂酰肌醇-3-激酶（PI 3 K）的受体活化。最 雷帕霉素的良好表征的作用是抑制p70 S6激酶 （p70 S6 K），一种翻译起始的调节因子， 4 E-BP 1是起始因子eIF-4 E的调节因子。 FRAP在一级氨基酸序列上与脂质家族相关 然而，它被认为是一种蛋白质， 激酶。 FRAP的潜在底物是4 E-BP 1和FRAP的调节剂。 蛋白磷酸酶活性 该应用程序旨在 调查FRAP的几个方面。 在目标一中，FRAP的职能 将通过识别新的底物进行研究。 这些底物与p70 S6 K和4 E- 将研究BP 1。 在Aim II中，FRAP结构域的作用， 结合FKBP 12-雷帕霉素。 在Aim III中， 与FRAP结合的多蛋白复合物将被纯化， 表征了 在目标IV中，FRAP与调节的关系 蛋白质磷酸酶将被研究。 通过了解详细的 FRAP的生化特性，蛋白质如何 翻译与细胞周期进程的关系将得到解答。