Control and function of the yeast RAM network

描述（由申请人提供）：细胞结构的控制涉及多种过程的协调，并与有丝分裂调节和细胞命运决定密切相关。这种控制对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。参与细胞形态发生的基本结构系统和调控机制是广泛保守的，对人类调控网络的关键理解来自出芽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非对称转录所必需的一种新的信号通路；它是高度保守的，但却鲜为人知。该项目的目标是确定RAM网络如何在形态发生控制中起作用，并确定将其活性与有丝分裂过程联系起来的机制。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。我们已经确定了控制Cbk1的重要机制，最近确定了它的磷酸化共识基序，这是Ndr激酶的独特和以前未知的。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点。我们还将确定RAM网络功能如何与有丝分裂协调。我们将专注于定义一个关键的调控修饰如何在M/G1转变过程中触发Cbk1的功能，并跟进我们的初步证据，即有丝分裂的polo样激酶Cdc5直接调节Cbk1和RAM网络。公共卫生相关性：所有器官都是由与组织相适应的细胞组成的。这需要严格控制细胞结构；在包括癌症在内的许多疾病中，这是疯狂的。这项拟议的研究旨在了解一个新发现的细胞形状控制系统是如何工作的。

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.