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

项目总结

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.