Regulation of PPM family serine/threonine phosphatases

Project Summary/Abstract Reversible protein phosphorylation controls essential cell fate decisions in all kingdoms of life. Because of this, the kinases and phosphatases that control phosphorylation are often dysregulated in disease and are attractive drug targets for therapeutics. The overarching goal of work in the laboratory is to address two of the biggest gaps in knowledge about reversible phosphorylation: how protein phosphatases are regulated and directed to the correct substrate- protein phosphorylation site(s). Our studies have focused on the PPM family of serine/threonine phosphatases, which stand out compared to the other evolutionarily distinct phosphatase families because they are widespread in bacteria, their activities are controlled by diverse cis- regulatory domains, and their genes are the most abundant serine/threonine phosphatases in the human genome (there are twenty isoforms). To uncover generalizable mechanistic principles of how phosphatases are controlled, we continue to study bacterial PPM phosphatases because of their importance to bacterial physiology and virulence (particularly through control of a stress response pathway called the general stress response), and because of the relative simplicity of the signaling pathways that they control. Over the next five years, we will additionally apply our breakthroughs in understanding of bacterial phosphatase regulation to phosphatases that are critical regulators of much more complex human signaling pathways, with a focus on MAP kinase signaling cascades. We will determine how the ancestral regulatory features of PPM phosphatases that were inherited from bacteria contribute to control of human phosphatases and how they have been elaborated to meet the needs of human signaling. Focusing on dephosphorylation of the activation loops of MAP kinases, some of the most highly regulated signaling nodes in human cells, enables comparison of how divergent phosphatase families target the same phosphorylation sites. Outcomes of these studies will reveal how phosphatses can be targeted with small-molecules for therapeutic benefit.