FRAP AND THE RAPAMYCIN SENSITIVE SIGNALING PATHWAY

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。人们对此已有很多了解 将细胞外信号连接到细胞核的信号通路，但 人们对这一规定涉及的确切机制知之甚少 蛋白质的合成。一些研究人员最近的研究表明， 研究表明，蛋白质翻译由一条信号通路调节，该信号通路 被免疫抑制剂雷帕霉素抑制。雷帕霉素在一种 与其结合蛋白FKBP-12的复合体与一种名为 FRAP(FKBP12-雷帕霉素相关蛋白)。通过一种未知的机制 FKBP12-雷帕霉素与FRAP结合干扰启动的信号转导 通过磷脂酰肌醇-3-激酶(PI3K)受体激活。最多的 雷帕霉素的典型作用是抑制p70S6激酶 (P70S6K)，翻译起始调节因子，并降低 启动因子eIF-4E的调节因子4E-BP1的磷酸化。 FRAF在初级氨基酸序列中与脂类家族相关 然而，包括PI3K在内的激酶被认为是一种蛋白质 激活剂。FRAP的潜在底物是4E-BP1和 蛋白磷酸酶活性。此应用程序的目标是 调查FRAP的几个方面。在Aim I中，FRAP的功能 将通过鉴定新的底物来进行研究。 这些底物与p70S6K和4E-2调控的关系 将对BP1进行研究。在AIM II中，FRAP结构域的作用 结合FKBP12-雷帕霉素将进行研究。在AIM III中，新的蛋白质 与FRAP结合的多蛋白复合体将被提纯并 特色化的。在目标四中，《财务行动计划》与规章的关系 将对蛋白质磷酸酶进行研究。通过了解详细的 FRAP的生化特性，蛋白质如何产生的基本问题 翻译与细胞周期进程的关系将得到回答。

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.