Tyrosine phosphorylation: from discovery to the kinome and beyond

Protein kinases (PKs) and phosphatases (PPs) are key components of protein phosphorylation based signaling networks in eukaryotic cells, and there has been long‐standing interest in the number of PKs and PPs needed to constitute intracellular signaling networks. We have used complete genome sequences to determine the total number of protein kinase genes (the kinome) in several eukaryotes. The human kinome has 518 PK genes; 478 of these PKs are in the ePK superfamily, and the remainder are atypical protein kinases, in a few small families. PKs constitute ~2% of all genes in budding and fission yeast, worms, flies and humans, and ~4% in plants. In metazoans 15–20% of all protein kinases are tyrosine kinases, but true tyrosine kinases are lacking in protozoans, such as the yeasts. The existence of tyrosine kinases in simple metazoans suggests that tyrosine phosphorylation evolved as a mechanism for intercellular communication. Mutations in PK and PP genes are increasingly found to be causal in human diseases; out of 518 PK genes >150 have been implicated in disease. Activating or inactivating mutations or over/underexpression of >120 tyrosine and serine kinases has been associated with human cancer. The prevalence of PKs involved in disease has led to intensive efforts in the pharmaceutical industry to develop specific PK inhibitors, and the first generation of kinase inhibitor drugs are now in the clinic for cancer therapy.