The reversible phosphorylation of proteins on serine, threonine, and tyrosine residues represents a fundamental strategy used by eukaryotic organisms to regulate a host of biological functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation. Levels of cellular protein phosphorylation are modulated both by protein kinases and phosphatases. Although the importance of kinases in this process has long been recognized, an appreciation for the complex and fundamental role of phosphatases is more recent. Through extensive biochemical and genetic analysis, we now know that pathways are not simply switched on with kinases and off with phosphatases. Rather, it is the balance of phosphorylation that is often critical. Protein phosphorylation can regulate enzyme function, mediate protein–protein interactions, alter subcellular localization, and control protein stability. Furthermore, kinases and phosphatases may work together to modulate the strength of a signal. Adding further complexity to this picture is the fact that both kinases and phosphatases can function in signaling networks where multiple kinases and phosphatases contribute to the outcome of a pathway. To fully understand this complex and essential regulatory process, the kinases and phosphatases mediating the changes in cellular phosphorylation must be identified and characterized.
A variety of approaches, including biochemical purification, gene isolation by homology, and genetic screens, have been successfully used for the identification of putative protein kinases and phosphatases. Now, the genomic sequencing of organisms promises to be a major contributor to this field. Valuable insight into these important enzymes has already emerged from the analysis of the yeast and worm genomes. In particular, genomic sequencing of Saccharomyces cerevisiae and Caenorhabditis elegans has revealed the kinase and phosphatase gene families that have arisen during the evolution of multicellular eukaryotes (Plowman et al. 1999). With the recent determination of the Drosophila sequence, we can now survey the genome of a second multicellular eukaryote for its repertoire of kinases and phosphatases. In this review, we will present our findings on the protein kinase and phosphatase gene families identified in the fly, together with an examination of the kinase/phosphatase signaling pathways functioning in flies, worms, and humans.