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Evolutionary adaptation and spatial organization of signaling in the Mitotic Exit Network

有丝分裂出口网络中信号的进化适应和空间组织

基本信息

批准号：
10331332
负责人：
Xiaoxue Zhou
金额：
$ 10万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331332
关键词：
Address Anaphase Binding Binding Sites Biological Models Case Study Cell Cycle Progression Cell Cycle Regulation Cell Nucleolus Cell division Cell membrane Cell physiology Cells Centrosome Complex Development Dimerization Disease Ensure Eukaryota Evolution Foundations Functional disorder Future Guanosine Triphosphate Phosphohydrolases Homologous Gene Human Hybrids Knock-out Label Life Light Location Logic Malignant Neoplasms Mammalian Cell Mammals Mediating Meiosis Mentors Mitochondria Mitogen-Activated Protein Kinases Mitosis Mitotic Modeling Nucleotides Organism Pathway interactions Phase Phosphoric Monoester Hydrolases Phosphotransferases Positioning Attribute Process Protein phosphatase Proteins Quantitative Microscopy Regulation Research Research Personnel Saccharomycetales Signal Pathway Signal Transduction Surface System Testing Training Work Yeasts base career comparative experimental study information processing inhibitor insight mutant optogenetics pressure prevent scaffold spindle pole body tool

项目摘要

Project Summary Sensing and processing information through signaling cascades is an essential part of cellular life. A few signaling cascades such as the MAP kinase and Hippo pathways are ubiquitous among eukaryotes yet perform different functions across organisms. Although these pathways are well-studied, how they evolve to take on new functions and adapt to new inputs remains poorly understood. The Mitotic Exit Network (MEN), a Ras-like GTPase signaling cascade and yeast homolog of the Hippo pathway, provides a unique opportunity to study this question. In the MEN, the same core signaling components operate in distinct manners under different developmental trajectories. During yeast mitosis which occurs through an asymmetric cell division called budding, the MEN is scaffolded onto the spindle pole bodies (SPB, the yeast equivalent of centrosomes) and responds to spindle position through its GTPase Tem1. During meiosis, where budding is suppressed and thus no need to sense spindle position, MEN signaling is no longer organized at the SPBs, and it is unclear whether Tem1 is still required for MEN activation and what signal it may respond to. To understand the adaptation of the MEN under distinct cellular contexts, this proposal will test the hypothesis that this adaptation is enabled partially by different activation mechanisms of the MEN kinase Cdc15, the effector kinase of Tem1, between mitosis and meiosis (Aim 1). In contrast to the drastic change in spatial organization of the MEN core components between mitosis and meiosis, the effector protein of the MEN, the phosphatase Cdc14, remains sequestered in the nucleolus prior to activation both in mitosis and meiosis. In fact, this nucleolar localization of Cdc14 is conserved from yeast to human. Sequestration of Cdc14 in the nucleolus could function either 1) to ensure tight inhibition of Cdc14’s phosphatase activity prior to activation or 2) to localize Cdc14 to dephosphorylate specific substrates in the nucleolus. To uncover the selection pressure that maintains this conserved nucleolar localization of Cdc14, this proposal will examine these two hypotheses by sequestering Cdc14 elsewhere in the cell and characterize the consequences first in yeast and then in mammalian cells (Aim 2). The experiments within both aims will be initiated during the K99 phase which also includes training of the candidate on new experimental systems such as yeast meiosis and mammalian cells, as well as the development and implementation of quantitative microscopy, proximity labeling and optogenetics. Furthermore, the candidate has assembled an outstanding mentor team to both advise her scientifically to facilitate progress of the project and prepare her for the transition to an independent investigator. Together, this proposal will create a strong foundation for an independent research career in understanding the evolution/adaptation and spatial organization of cellular signaling.

项目总结