The role of AKAP350 splice variants in cellular stress response
Mason, Twila Annette
Every organism experiences stress, which occurs when there is a perturbation of homeostasis. Individual cells experience stress throughout their physiological processes and have developed many mechanisms to cope with that stress. Proper response to stress is critical for cell and organism survival. Improper stress response can lead to disease development or progression. This body of work investigates the roles of AKAP350 splice variants in cellular stress response. AKAPs (A-Kinase Anchoring Proteins) are large scaffolding proteins that serve as cell signaling centers. The AKAP9 gene produces four known splice variants: yotiao, AKAP350A, AKAP350B, and AKAP350C. In my studies, I used Darinaparsin-treatment as a tool to further investigate the mechanisms of stress granule formation, maintenance, and dispersal, including the localization of AKAP350A, during these processes. I also discovered that caprin-1 is phosphorylated within the AKAP350A complex in response to ultraviolet light irradiation. Next, I examined the mitochondrial targeting of AKAP350C and its role in the regulation of mitochondrial dynamics and stress response. I also discovered a third, novel PKA-binding site within the AKAP350 splice variants. Lastly, I developed AKAP9-null and AKAP9F/F mice as tools for studying the roles of AKAP9 proteins in organism development and disease. In conclusion, AKAP9 splice variants play dual roles in cells during non-stress and stressed conditions, and are required for proper stress response. In summary, I discovered new insights into stress response regulation by AKAP350 splice variants.