The Eukaryotic Protein Kinase Superfamily and the Emergence of Receptor Tyrosine Kinases

Abstract

The presence of tightly bound phosphate in proteins was discovered in 1883 and covalent attachment of phosphate to proteins in 1906, but this important posttranslational modification had been “invented” by evolution billion years before this in early prokaryotes. Tyrosine phosphorylation, as distinct from serine and threonine phosphorylation, was discovered in 1979 but appears to have arisen in single-celled eukaryotes that were the antecedents of the first multicellular animals. Sophisticated cell-cell communication was a sine qua non for the emergence of multicellular organisms, and the development of cell surface receptor systems that utilize tyrosine phosphorylation for transmembrane signal transduction and intracellular signaling seems likely to have been a crucial event in the evolution of metazoans. Like all types of protein phosphorylation, tyrosine phosphorylation can regulate proteins in multiple ways, but the most important function of phosphotyrosine (P.Tyr) is to serve as a docking site that promotes a specific interaction between a tyrosine-phosphorylated protein and another protein that contains a P.Tyr-binding domain, such as an SH2 domain. Once a surface receptor tyrosine kinase (RTK) is activated and becomes autophosphorylated upon binding an extracellular ligand, P.Tyr docking interactions of this sort initiate signal transduction through cytoplasmic signaling pathways and, as a consequence, elicit specific cellular outcomes. This chapter reviews the emergence of the protein kinase family in eukaryotes and how tyrosine kinases and, in particular, receptor tyrosine kinases that could be activated upon binding of an extracellular ligand evolved to serve key roles in transmembrane signal transduction.