Control and function of the yeast RAM network

酵母 RAM 网络的控制和功能

• 批准号: 7445600
• 负责人: ERIC Lyle WEISS
• 金额: $ 26.25万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7445600
• 关键词: Actins; Address; Adopted; Architecture; Biological; Cell Cycle; Cell Fate Control; Cell Proliferation; Cell Shape; Cell physiology; Cells; Cellular Morphology; Chemicals; Classification; Consensus; Coupled; Defect; Disease; Embryonic Development; Employee Strikes; Enzymes; Event; Family; Genes; Genetic; Genetic Transcription; Genome; Goals; Golgi Apparatus; Growth; Human; Investigation; Link; Localized; Malignant Neoplasms; Mitosis; Mitotic; Modification; Morphogenesis; Organ; Paramecium; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Process; Protein Kinase; Proteins; Public Health; Regulation; Research; Role; Saccharomycetales; Secretory Vesicles; Shapes; Signal Pathway; Site; System; Tissues; Work; Yeasts; cell growth; daughter cell; follow-up; human PLK1 protein; human disease; migration; novel; research study; trafficking

DESCRIPTION (provided by applicant): The control of cell architecture involves coordination of diverse processes, and is closely coupled with mitotic regulation and cell fate determination. This control is fundamental to embryonic development and tissue function; its derangement is an important aspect of numerous human diseases. Essential structural systems and regulatory mechanisms involved in cell morphogenesis are broadly conserved, and critical understanding of human regulatory networks has derived from studies of related pathways in budding yeast. The yeast RAM network is a novel signaling pathway required for polarized growth and asymmetric transcription during exit from mitosis; it is highly conserved, but poorly understood. This project's goals are to determine how the RAM network functions in morphogenesis control and to define the mechanisms that link its activity to mitotic progress. Our efforts largely focus on Cbk1, an Ndr/LATS family protein kinase; these enzymes are conserved from Paramecium to humans. We have defined mechanisms important for control of Cbk1 and recently determined its phosphorylation consensus motif, which is distinctive and previously unknown for Ndr kinases. Using a combination of hypothesis-driven studies and genome-scale systematic genetic interaction analysis we will identify regulatory targets of the kinase that are relevant to cell morphogenesis. We will also determine how RAM network function is coordinated with mitosis. We will focus on defining how a critical regulatory modification triggers Cbk1's function during the M/G1 transition and following up on our preliminary evidence that the mitotic polo-like kinase Cdc5 directly regulates Cbk1 and the RAM network. PUBLIC HEALTH RELEVANCE: All organs are composed of cells that adopt shapes that are appropriate for the tissue. This requires exacting control of cell architecture; in numerous diseases, including cancer, this is deranged. This proposed research seeks to understand how a newly-discovered system for cell shape control works.

描述（由申请人提供）：细胞结构的控制涉及不同过程的协调，并且与有丝分裂调节和细胞命运决定密切相关。这种控制对于胚胎发育和组织功能至关重要。它的紊乱是许多人类疾病的一个重要方面。细胞形态发生所涉及的基本结构系统和调节机制广泛保守，对人类调节网络的批判性理解源自对芽殖酵母相关途径的研究。酵母 RAM 网络是有丝分裂退出过程中极化生长和不对称转录所需的新型信号通路；它高度保守，但了解甚少。该项目的目标是确定 RAM 网络如何在形态发生控制中发挥作用，并定义将其活动与有丝分裂进展联系起来的机制。我们的工作主要集中在 Cbk1，一种 Ndr/LATS 家族蛋白激酶；这些酶从草履虫到人类都是保守的。我们已经定义了控制 Cbk1 的重要机制，并且最近确定了其磷酸化共有基序，该基序对于 Ndr 激酶来说是独特且以前未知的。通过结合假设驱动的研究和基因组规模的系统遗传相互作用分析，我们将确定与细胞形态发生相关的激酶的调控靶标。我们还将确定 RAM 网络功能如何与有丝分裂协调。我们将重点关注确定关键的调控修饰如何在 M/G1 转换期间触发 Cbk1 的功能，并跟进我们的初步证据，即有丝分裂 Polo 样激酶 Cdc5 直接调节 Cbk1 和 RAM 网络。公共卫生相关性：所有器官均由具有适合组织形状的细胞组成。这需要对细胞结构进行严格控制；在包括癌症在内的许多疾病中，这种情况都是紊乱的。这项拟议的研究旨在了解新发现的细胞形状控制系统是如何工作的。