UC San Diego

As a central regulatory hub, protein kinase A (PKA) coordinates numerous biological processes, including discrete effects on metabolic enzymes all the way to global effects on organism growth and development. Given the diversity of roles PKA can play in normal physiology it is not surprising that dysregulation of PKA leads to diverse pathophysiology and disease. While PKA is one of the most studied kinases, its role in diseases has remained largely unknown. With this dissertation, I aim to map the contributions of the Gαs-PKA pathway in disease from multiple perspectives. First, I aim to unify the view of PKA-driven pathophysiology by utilizing mutational data from hereditary diseases and cancer databases to define a family of diseases known as the Gαs-PKA pathway signalopathies. Further I utilize evidence from the scientific literature to bring functional understanding to these diverse disease states. Second, I leverage our genetic understanding of PKA pathway mutations to develop several transgenic mouse models of cancer, providing evidence of the role of GNAS in cancer initiation and tools for application in multiple tissue contexts. Finally, I take advantage of affinity purification mass spectrometry (AP-MS) approaches to identify novel PKA interactors. I uncover several functional themes and ultimately focus on specific RNA binding proteins interactions that mediate new mechanisms of posttranscriptional regulation. In total, this dissertation makes important progress towards the understanding of PKA-driven disease, providing a framework for the advancement of the field and ultimately unique opportunities for identifying therapeutic interventions.