Mechanisms that coordinate cell size and mitotic entry

各种各样的细胞类型延迟细胞周期转换，直到它们达到临界大小阈值，但 测量大小并将此信息传递给核心细胞周期机制的机制 大部分都是未知的。裂变酵母细胞由于信号传导而在比表面积上分裂， 大脑皮层上的多蛋白质结构称为“节点”。节点包含保守的细胞周期 调节剂包括蛋白激酶Cdr 2、Cdr 1和Wee 1，它们以线性， 基因定义的途径来调节有丝分裂进入。最近，我们发现节点也 含有保守的GTdR Arf 6，并发现Arf 6通过Cdr 2- Cdr 1-Wee 1通路。我们还不知道细胞内的组装或信号转导机制， 结我们将利用强大的遗传、生物化学和定量分析技术， 成像方法。破坏节点信号的突变导致细胞在特定的时间分裂。 体积，而不是表面积。基于几条证据，我们假设， Cdc 25在细胞核中的受调节的积累代表了体积传感器。我们将测试 细胞大小控制的模型来自不同的途径，每种途径都监控不同的方面 细胞的几何形状。我们将重点关注细胞周期调控的基本过程， 对信号转导的空间控制具有广泛的意义，因为高阶簇和 在整个细胞生物学中，节点样结构正在成为信号转导的关键位点。 该基金的具体目标是：（1）明确Cdr 2节点组装的分子机制 和功能，（2）确定Arf 6 GTdR在分裂时如何调节Cdr 2节点和细胞大小，以及 (3)测试Cdc 25和Cdr 2途径监测细胞几何形状的不同方面的模型。 成功完成这些目标将通过确定如何定义 信号通路响应于细胞生长的不同方面。此外，信号 我们发现的机制将为规模如何控制其他生物的活动提供见解。 生物系统。

A wide variety of cell types delay cell cycle transitions until they reach a critical size threshold, but the mechanisms that measure size and transmit this information to the core cell cycle machinery are largely unknown. Fission yeast cells divide at a specific surface area due to signaling by large, multi-protein structures called “nodes” at the cortex. Nodes contain conserved cell cycle regulators including the protein kinases Cdr2, Cdr1, and Wee1, which function in a linear, genetically defined pathway to regulate mitotic entry. Recently, we discovered that nodes also contain the conserved GTPase Arf6 and found that Arf6 promotes mitotic entry through the Cdr2- Cdr1-Wee1 pathway. We do not know the mechanisms of assembly or signal transduction within nodes. We will address key open questions using powerful genetic, biochemical, and quantitative imaging approaches. Mutations that abolish node signaling cause cells to divide at a specific volume, as opposed to surface area. Based on several lines of evidence, we hypothesize that regulated accumulation of Cdc25 in the cell nucleus represents the volume sensor. We will test the model that cell size control emerges from different pathways, each monitoring distinct aspects of cell geometry. We will focus on the fundamental process of cell cycle regulation, but our work has broad implications for spatial control of signal transduction because higher-order clusters and node-like structures are emerging as critical sites of signal transduction throughout cell biology. The specific aims of this grant are to: (1) define the molecular mechanism of Cdr2 node assembly and function, (2) determine how Arf6 GTPase regulates Cdr2 nodes and cell size at division, and (3) test the model that Cdc25 and Cdr2 pathways monitor distinct aspects of cell geometry. Successful completion of these goals will advance scientific knowledge by identifying how defined signaling pathways respond to different aspects of cell growth. Moreover, the signaling mechanisms that we uncover will provide insights for how size controls the activity of other biological systems.