Ras protein signaling and the control of cell growth

Ras 蛋白信号传导和细胞生长的控制

• 批准号: 7533495
• 负责人: Paul K Herman
• 金额: $ 28.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533495
• 关键词: Address; Aging; Apoptosis; Autophagocytosis; Autophagosome; Biology; Cell Proliferation; Cell Survival; Cells; Complex; Cues; Cyclic AMP-Dependent Protein Kinases; Cytoplasmic Protein; Data; Degradation Pathway; Development; Disease; Ensure; Eukaryota; Eukaryotic Cell; Event; Future; G0 Phase; Growth; Growth Factor; Human; Huntington Disease; Interphase Cell; Knowledge; Link; Lysosomes; Maintenance; Malignant Neoplasms; Membrane; Molecular; Nutrient; Organelles; Organism; Output; Pathway interactions; Phase; Phosphorylation; Process; Protein Kinase; Regulation; Research Personnel; Resistance; Rest; Role; Saccharomyces cerevisiae; Signal Pathway; Signal Transduction; Stress; Structure; Translating; Vacuole; Vesicle; Work; Yeasts; cell growth; insight; interest; pathogen; ras Proteins; research study; response

A thorough description of the GO-like resting states of eukaryotic cells is essential for a complete understanding of the mechanisms controlling cell proliferation. Towards this end, we have been studying how the Ras/cAMP-dependent protein kinase (PKA) signaling pathway regulates the biology of one particular resting state, stationary phase in Saccharomyces cerevisiae. Interestingly, we have found that Ras/PKA signaling activity regulates autophagy, a highly conserved, degradative pathway required for resting cell survival. Autophagy is important for normal development in multicellular organisms and recent studies have linked this process to aging, programmed cell death, cancer, Huntington'.s disease and the cellular response to pathogens. Our recent data indicate that this Ras/PKA pathway directly targets a key regulator of autophagy, the Atg1 protein kinase. Interestingly, other work has shown that Atg1 is also regulated by two additional signaling pathways that have a central role in the control of eukaryotic cell growth. These latter two pathways involve the highly conserved Tor and AMP-activated (Snfl) protein kinases. The experiments here will examine how the Ras/PKA, Tor and Snf1 pathways work together to regulate Atg1 activity, and thus the induction of autophagy in eukaryotic cells. In addition, we will use autophagy, and other activities, as readouts in an attempt to develop a better understanding of how the activities of these three signaling pathways are coordinated to bring about the proper control of cell growth. Since the autophagy machinery is highly conserved, it is likely that the regulatory paradigms identified here will be used in other eukaryotes. Thus,:these studies could provide important insights into how this process might be manipulated in clinically useful ways in humans. The Specific Aims of this proposal are: 1) to determine the mechanism by which PKA phosphorylation regulates the activity of the Atg1 protein kinase complex; and 2) to examine the interplay between the Ras/PKA, Tor and Snf1 signaling pathways during the control of autophagy and cell growth.

对真核细胞的类似静止状态的透彻描述对于完整的 了解控制细胞增殖的机制。为此，我们一直在研究 RAS/CAMP依赖性蛋白激酶（PKA）信号通路如何调节一个人的生物学 特定的休息状态，酿酒酵母的固定阶段。有趣的是，我们发现 RAS/PKA信号传导活动调节自噬，这是一种高度保守的降解途径 静止的细胞存活。自噬对于多细胞生物的正常发育很重要，最近 研究将这一过程与衰老，程序性细胞死亡，癌症，亨廷顿氏病和 细胞对病原体的反应。 我们最近的数据表明，此RAS/PKA途径直接针对自噬的关键调节剂，即 ATG1蛋白激酶。有趣的是，其他工作表明，ATG1也受到另外两个 在控制真核细胞生长中具有核心作用的信号通路。后两个 途径涉及高度保守的TOR和AMP激活（SNFL）蛋白激酶。这里的实验 将检查RAS/PKA，TOR和SNF1途径如何共同调节ATG1活性，从而如何调节ATG1活性 在真核细胞中诱导自噬。此外，我们将使用自噬和其他活动，作为 读数是为了更好地了解这三个信号的活动如何 途径是协调的，以适当控制细胞生长。由于自噬机械是 高度保守的，此处确定的调节范例可能会在其他真核生物中使用。 因此，：这些研究可以提供有关如何在临床上操纵该过程的重要见解 人类有用的方法。 该提案的具体目的是：1）确定PKA磷酸化的机制 调节ATG1蛋白激酶复合物的活性； 2）检查 在控制自噬和细胞生长过程中，RAS/PKA，TOR和SNF1信号通路。