Regulatory Mechanisms of PP2A Family Phosphatases

The overall goal of our research program is to gain a comprehensive understanding of the molecular mechanisms underlying the regulation of protein phosphatase 2A (PP2A) family phosphatases, including PP2A, PP4, and PP6, in response to environmental signals. Reversible protein phosphorylation is a major regulatory mechanism by which cells respond to their environment and regulate cellular behavior. Although much is known about the regulation of protein kinases in specific signaling pathways, the regulation of protein phosphatases in response to environmental signals to counteract kinase functions is not well-established. Unlike kinases, serine/threonine phosphatases are promiscuously active, and their specificity is largely governed by associated proteins, which makes their analysis exceedingly difficult. Our recent efforts to address this major knowledge gap have led to significant conceptual advancements in understanding how PP2A family phosphatases respond to the extracellular environment. We have developed an innovative view of serine-threonine phosphatase complexes, proposing that these complexes are unstable and constantly regulated by disassembly and reassembly. Additionally, we found that specific regulatory subunits are induced in response to specific stimuli to determine PP2A substrate specificity and influence physiological functions. A key discovery in our lab was the identification of a regulatory subunit of PP6, SAPS3, which is essential for the dephosphorylation of AMPK in response to metabolic environmental signals. This discovery has enabled us to further study the molecular mechanisms underlying SAPS3 complex assembly and the functional implications of phosphatase complexes in cellular operations. Over the next five years, our research will continue to elucidate the molecular mechanisms by which the SAPS3-containing PP6 phosphatase complex assembles in response to extracellular signals and determine its cellular and systemic functions in response to environmental stimuli using cellular systems and animal models. For the long-term pursuit of studying PP2A family phosphatases, we will also identify other novel phosphatase complexes involved in specific signaling pathways. The accomplishment of these studies will provide transformative insights into the molecular mechanisms by which cells respond to their environment and will lay an essential framework for the development of novel targeted therapies to restore cellular homeostasis.