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

• 批准号: 10746190
• 负责人: Xiaoxue Zhou
• 金额: $ 11.06万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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/10746190
• 关键词: Advisory Committees; Biochemistry; Biological Models; COVID-19 pandemic; Cell division; Centrosome; Development; Development Plans; Disease; Eukaryota; Evolution; Foundations; Functional disorder; Funding; Guanosine Triphosphate Phosphohydrolases; Homologous Gene; Human; In Vitro; Knowledge; Life; Malignant Neoplasms; Manuscripts; Meiosis; Mentors; Mitogen-Activated Protein Kinases; Mitosis; Mitotic; Organism; Pathway interactions; Phosphotransferases; Positioning Attribute; Protein Biochemistry; Protein phosphatase; Regulation; Research; Research Personnel; Secure; Signal Pathway; Signal Transduction; Testing; Training; Work; Yeasts; career; career development; information processing; member; pandemic disease; reconstruction; scaffold; single molecule; skills; spindle pole body; timeline

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. COVID-19 pandemic related research restriction and the passing of my mentor Dr. Angelika Amon during the pandemic severely disrupted my research progress and delayed my career development plans. While I made significant progress toward the aims laid out in my original K99 proposal and am currently preparing a manuscript on the project, my transition to independence was delayed for a year relative to the originally proposed timeline. A funded extension will allow me to develop critical skills in protein biochemistry, in vitro reconstruction, and yeast meiosis to dissect the mechanisms of Cdc15 regulation in mitosis versus meiosis. I will accomplish this with the guidance and training from my mentor Dr. Stephen Bell (biochemistry, single molecule, and in vitro reconstruction) and Dr. Elçin Ünal (yeast meiosis, member of my advisory committee). Furthermore, a funded extension will also allow me to complete my current search in securing an academic position and enable my transition into an independence investigator. In summary, the additional training and support I will receive during the extended K99 period will equip me with the knowledge and skills necessary to study the mechanisms underlying signaling adaptation of the MEN in different cellular contexts and create a strong foundation for an independent research career in understanding the evolutionary adaptation of cellular signaling.

项目概要 通过信号级联感知和处理信息是细胞生命的重要组成部分。 MAP 激酶和 Hippo 通路等信号级联在真核生物中普遍存在 尽管这些途径已被充分研究，但它们是如何进化的。 对于承担新功能和适应新输入的有丝分裂退出网络（MEN）仍然知之甚少。 Ras 样 GTPase 信号级联和 Hippo 途径的酵母同源物，提供了独特的机会 研究这个问题，在 MEN 中，相同的核心信号组件以不同的方式运行。 在酵母有丝分裂过程中，通过不对称的细胞分裂发生不同的发育轨迹。 称为出芽，MEN 被搭建在纺锤体极体上（SPB，相当于酵母的中心体） 并通过其 GTPase Tem1 对纺锤体位置作出反应 在减数分裂过程中，出芽受到抑制，并且 因此无需感测纺锤体位置，MEN 信号不再在 SPB 上组织，目前还不清楚 MEN 激活是否仍需要 Tem1 以及它可能响应什么信号。 MEN 在不同的细胞环境下的适应，该提案将测试这种适应的假设 部分是由 MEN 激酶 Cdc15（Tem1 的效应激酶）的不同激活机制实现的， 有丝分裂和减数分裂之间的研究限制和我的导师的去世。 疫情期间Angelika Amon博士严重扰乱了我的研究进展并耽误了我的职业生涯 虽然我在最初的 K99 提案中提出的目标方面取得了重大进展，但 目前正在准备该项目的手稿，我向独立的过渡被推迟了一年 相对于最初提出的时间表，资助的延期将使我能够发展蛋白质方面的关键技能。 生物化学、体外重建和酵母减数分裂来剖析 Cdc15 调节机制 有丝分裂与减数分裂我将在我的导师斯蒂芬·贝尔博士的指导和培训下完成这一任务。 （生物化学、单分子和体外重建）和 Elçin Ünal 博士（酵母减数分裂，我的成员） 此外，受资助的延期还将使我能够完成当前的搜索 获得学术职位并使我能够转变为独立调查员总而言之， 我在 K99 延长期间将接受的额外培训和支持将使我掌握相关知识 以及研究 MEN 在不同细胞中的信号适应机制所必需的技能 背景并为理解进化的独立研究生涯奠定坚实的基础 细胞信号传导的适应。