Protein Serine/Threonine Phosphatase Inhibitors and Human Disease

This chapter focuses on new information on the mode of action of phosphatase inhibitors and discusses their potential contributions to the pathophysiology of human disease. Emerging studies suggest that some phosphatase inhibitors physically associate with cellular phosphatase complexes composed of a catalytic subunit bound to one or more regulatory proteins that restrict the actions of the phosphatases to control specific cellular events. The functions of these phosphatase inhibitors are in turn controlled by their expression, reversible phosphorylation, and dynamic association with target protein phosphatases. In this manner, endogenous serine/threonine phosphatase inhibitors achieve both spatial and temporal control of phosphoproteins that regulate normal cell physiology, and growing evidence suggests that aberrant expression and activity of phosphatase inhibitors may be associated with many human diseases. The availability of protein and non-protein inhibitors of protein serine/threonine phosphatases has provided researchers with an extensive toolkit to study the role of phosphatases and phosphatase inhibitors in modulating the mammalian physiology. Rapid progress is also being made in the understanding of cellular phosphatase complexes and their functions. In addition, the mechanisms that regulate the expression and activity of phosphatase inhibitors and their mode of action in controlling specific pools of cellular protein phosphatases are being actively investigated.