Control and function of the yeast RAM network

描述(申请人提供)：细胞结构的控制涉及不同过程的协调，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是基本的；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对发芽酵母相关途径的研究。酵母RAM网络是一个新的信号通路，在有丝分裂过程中需要极化生长和不对称转录；它是高度保守的，但人们对它知之甚少。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，并确定将其活动与有丝分裂进程联系起来的机制。我们的工作主要集中在Cbk1，一个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，并最近确定了它的磷酸化共识基序，这对于NDR激酶来说是独特的，以前未知的。利用假说驱动的研究和基因组规模的系统遗传相互作用分析相结合的方法，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相协调。我们将集中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‘S的功能，并跟进我们的初步证据，即有丝分裂马球样激酶CDC5直接调控CBK1和RAM网络。与公共卫生相关：所有器官都由采用适合组织的形状的细胞组成。这需要严格控制细胞结构；在包括癌症在内的许多疾病中，这都是错综复杂的。这项拟议的研究试图了解一种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.