Chapter 97 - MAP Kinase Phosphatases

Abstract

Mitogen-activated protein kinases (MAPKs) constitute a highly conserved family of enzymes that regulate a diverse array of physiological processes in mammalian cells and tissues. These include cell proliferation and differentiation, development, immune function, stress responses, and cell death. This chapter describes the characterization, roles, and properties of protein phosphatases that participate in the regulation of MAPK activities. Protein serine/threonine phosphatases (PSTPs) can affect the outcome of MAPK signaling by intervention at a number of points within these signaling pathways, but this chapter will focus only on those PSTPs that have been shown to dephosphorylate the MAPKs themselves. Genetic and biochemical experiments in a wide variety of model organisms have revealed that a complex network of protein phosphatases controls MAPK activities. These studies have revealed important regulatory principles which extend from yeast to man. Studies in S. cerevisiae were the first to demonstrate that a single MAPK can be subject to regulation by all three major classes of protein phosphatase, including type 2 serine/threonine phosphatases, classical cysteine-dependent tyrosine phosphatases, and dual-specificity protein phosphatases, and also to suggest that these enzymes could facilitate cross-talk between distinct signaling pathways. The coordinated regulation of distinct MAPKs is crucial to the regulation of important physiological endpoints such as immune function and metabolic homeostasis, indicating that MKPs act as key integration points in the regulation of MAPK signaling.