Serine−Threonine Protein Phosphatase Inhibitors:  Development of Potential Therapeutic Strategies

The regulation of cellular processes by the modulation of protein phosphorylation/dephosphorylation is fundamental to a large number of, if not all, physiological functions. The phosphorylation level of a given protein is governed by the balance between two enzyme activities: protein kinases which transfer phosphate from ATP to the protein (phosphorylation) and protein phosphatases which catalyze the reverse reaction (dephosphorylation). It is considered that over 30% of all cellular proteins are subject to phosphorylation at one or more residues, and eukaryotic cells have been estimated to possess 575 kinase genes or 2% of the genome (given that the estimated total number of genes is 30−40000). Protein kinases are integral components of cell signal transduction pathways, and the regulation of many of these protein kinases in response to extracellular signals is well understood. Virtually every disease has, at its core, a deficiency in cellular signaling such that protein kinases are considered viable targets for the design of novel therapeutics. Understanding the role of protein phosphatases in these systems has lagged considerably behind that of protein kinases. Indeed, until recently, protein phosphatases were considered relatively nonspecific, unsophisticated enzymes that existed only to reverse the actions of protein kinases. It is now widely acknowledged that the regulation of protein phosphorylation requires the coordinated control of both kinases and phosphatases and that the regulation of phosphatases is as complex and elegant as that of kinases, perhaps more so. Genomic data suggests that there are 13 genes and 15 proteins in the PPP family and an additional 10 genes in the PPM family. Thus the serine/threonine protein phosphatases comprise <0.1% of the human genome. To view protein phosphatases as simply molecular "off switches" is clearly an oversimplification of their roles as "rheostats" governing the fine control of some processes, and in some cases the major point of control is emerging. Consequently, protein phosphatases are beginning to be linked with the etiology or control of disease processes. In the past decade there has been a substantial increase in effort to elucidate their biological roles, and thus their potential medical implications. Protein phosphatases that dephosphorylate tyrosine or serine and threonine represent distinct classes of enzyme, and each class warrants separate consideration. In this review, discussion is limited to only the serine/threonine protein phosphatases. We discuss some of the opportunities, implications, and limitations of utilizing the "inhibition of serine−threonine protein phosphatases as a therapeutic strategy".