Protein Kinases and Protein Phosphatases in Signal Transduction Pathways

Abstract

Protein phosphorylation has become a central focus of drug discovery as the result of the identification and validation of promising therapeutic targets such as protein kinases, protein phosphatases, and phosphoprotein binding domains. 1–24 With respect to such protein phosphorylation therapeutic targets, significant progress has been made in mapping the signal transduction pathways involved in disease, including in particular the molecular genesis and/or sustainment of various cancers, and several inflammatory, immune, metabolic, and bone diseases. Protein phosphorylation is an extraordinarily important component of life processes, including various signal transduction pathways underlying cellular proliferation, differentiation, metabolism, survival, motility, and gene transcription. Protein phosphorylation is a complex phenomenon, with molecular triggering, compensatory mechanisms, and both spatial and temporal factors contributing to the biological specificity and functional endpoints within the cellular milieu. The global phosphorylation state of proteins in cells is fundamentally impossible to decipher at high resolution, even though sophisticated methods (e.g., mass spectrometry, functional interaction traps, affinity chromatography) are emerging that can be used to analyze the so-called phosphoproteome. In this chapter, protein phosphorylation is described relative to our current understanding of the biology of protein kinase, protein phosphatase, and the phosphoprotein-interacting domain containing intracellular proteins. In addition a few noteworthy examples of drug discovery focused on developing small-molecule inhibitors of such therapeutic targets are described.