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 通过信号级联向传感和处理信息是细胞寿命的重要组成部分。几个 诸如MAP激酶和河马途径之类的信号传导级联反应在真核生物中无处不在 在各种生物体之间执行不同的功能。尽管这些途径是经过充分研究的，但它们如何发展为 采取新功能并适应新的投入仍然知之甚少。有丝分裂出口网络（男性）， 类似RAS的GTPase信号传导级联和河马途径的酵母同源物为您提供了独特的机会 研究这个问题。在男人中，相同的核心信号组件以不同的方式运作 不同的发展轨迹。在酵母有丝分裂中，通过不对称细胞分裂发生 这些人被称为萌芽，将脚手架脚手架上的纺锤体体（SPB，相当于中心体的酵母） 并通过其GTPase TEM1响应主轴位置。在减数分裂期间，萌芽被抑制和 因此，无需感知纺锤体位置，男人的信号不再是在SPB处组织的，目前尚不清楚 男性激活是否仍需要TEM1及其可能响应的信号。理解 在不同的细胞环境下，男人的适应，该提案将检验以下假设。 由MEN激酶Cdc15的不同激活机制（TEM1的效应子激酶）的不同激活机制部分启用 在有丝分裂和减数分裂之间。 COVID-19-19与我的精神的大流行相关研究限制和通过 Angelika Amon博士在大流行期间严重破坏了我的研究进展，并推迟了我的职业生涯 发展计划。虽然我朝着原始K99提案中规定的目标取得了重大进展，并且 目前正在准备该项目的手稿，我向独立的过渡延迟了一年 相对于原始提议的时间表。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调节的机制 有丝分裂与减数分裂。我将在我的心理斯蒂芬·贝尔博士的指导和培训中完成此操作 （生物化学，单分子和体外重建）和Elçinünal博士（酵母减数分裂，我的成员 咨询委员会）。此外，资助的扩展名还可以使我完成当前的搜索 确保学术职位并使我过渡到独立调查员。总而言之， 在扩展的K99期间，我将获得的其他培训和支持将使我能够了解知识 和研究男性在不同细胞中的信号适应机制所必需的技能 环境并为了解进化的独立研究职业创造了强大的基础 细胞信号的适应。