Mechanisms Regulating the Protein Kinases of Saccharomyces cerevisiae

Reversible protein phosphorylation is a ubiquitous post- translational modification in all eukaryotes. It is critically in- volved in the regulation of nearly all cellular processes and signaling pathways. Protein kinases, the enzymes that catalyze the phosphotransfer reaction, constitute one of the largest protein families, accounting for approximately 2% of the genes in any given eukaryotic genome (122). Few of these kinases are constitutively active; unregulated activity would be deleterious or lethal to cells in the cases of most protein kinases. Cells have thus developed a variety of finely tuned mechanisms to pre- cisely control the activities of these enzymes. We aim here to characterize the regulatory mechanisms governing the activities of protein kinases in Saccharomyces cerevisiae on a genome-wide scale. We do not attempt to re- view comprehensively the substrates, target sequences, or downstream effects of these kinases. Using yeast as a model system to analyze the regulation of protein kinases on a global scale has advantages. Yeast expresses a limited number of protein kinases relative to metazoans, and the regulation of most yeast kinases has been characterized to some extent and in some cases in exquisite detail. However, the relative sim- plicity of the yeast kinase collection also presents a limitation: entire families of protein kinases found in other eukaryotes (for example, the receptor- and Src-like tyrosine kinases present in metazoans) are not represented in yeast (122). Nonetheless, reviewing the regulatory paradigms of kinases in yeast is a feasible and illustrative task. Using yeast as a model, the information reviewed herein suggests that organisms utilize a finite number of regulatory paradigms in controlling their complement of kinases. In fact, this is very much a story of recurrent themes, with similar modes of regulation arising in disparate kinase families. While a cadre of regulatory motifs can be found controlling the ac- tivities of constituent members of nearly all evolutionary fam- ilies of protein kinases, distinct patterns are readily apparent. For example, activating interactions with partner proteins (e.g., calmodulin, Cdc42, and cyclins) and phosphorylation within and outside the activation loop are common regulatory para- digms. Knowledge of regulatory motifs common to specific protein kinase families can be instructive in guiding experi- ments intended to ascertain the regulation of related, unchar- acterized kinases. NAMES, FAMILIES, AND PHYLOGENY