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.

项目摘要 通过信号级联来感知和处理信息是细胞生命的重要组成部分。几 信号级联如MAP激酶和Hippo通路在真核生物中普遍存在， 在生物体中发挥不同的功能。尽管这些途径已经得到了很好的研究，但它们是如何演变成 承担新的职能和适应新的投入仍然知之甚少。有丝分裂出口网络（MEN）， Ras样GT3信号级联和Hippo途径的酵母同系物，提供了一个独特的机会， 研究这个问题。在MEN中，相同的核心信令组件以不同的方式操作， 不同的发展轨迹。在酵母有丝分裂过程中， 这种被称为出芽的结构，MEN被搭建在纺锤体的极体上（SPB，相当于酵母的中心体） 并通过其GTSTem1响应主轴位置。在减数分裂过程中，出芽被抑制， 因此不需要检测纺锤体的位置，MEN信号不再在SPB上组织， MEN激活是否仍然需要Tem1以及它可能响应什么信号。了解 适应的MEN在不同的细胞环境下，这项建议将测试的假设，这种适应 部分是由MEN激酶Cdc15，Tem1的效应激酶， 有丝分裂和减数分裂之间的联系2019冠状病毒病相关研究限制和我的导师去世 博士Angelika Amon在大流行期间严重扰乱了我的研究进度，并推迟了我的职业生涯 发展规划虽然我在实现我最初的K99提案中提出的目标方面取得了重大进展， 我目前正在准备一份关于这个项目的手稿，我向独立的过渡被推迟了一年 相对于最初提出的时间轴。一个资助的扩展将使我能够发展蛋白质的关键技能 生物化学，体外重建和酵母减数分裂，以剖析Cdc15调控的机制， 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目标 （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） 咨询委员会）。此外，一个资助的扩展也将使我能够完成我目前的搜索， 确保学术地位，使我能够过渡到一个独立的调查员。总而言之， 在K99延长期内，我将接受额外的培训和支持，这将使我掌握以下知识 以及研究MEN在不同细胞中的信号适应机制所必需的技能。 背景和创造一个独立的研究生涯在理解进化的坚实基础 适应细胞信号。