Introduction Historical Perspective

Few molecules have been more closely linked to cancer than the protein tyrosine kinases. Tyrosine phosphorylation and the tyrosine kinase enzymes which create phos-photyrosine residues in their substrate proteins were discovered during studies of the oncogenic factors in tumour viruses. The identification of v-Src as the transforming factor of the Rous sarcoma virus and the recognition of its activity as a protein tyrosine kinase conceptualized the oncogene theory of tumorigenesis, creating a model which has dominated much of cancer research over the past two decades. The importance of the work on viral oncogenes in the early research on tyrosine phosphorylation is shown by an accounting of landmark events in this area (Table 1) (Hunter, 1998). The discovery of a cellular counterpart (c-Src) of the viral Src (v-Src) tyrosine kinase indicated a much broader role for these enzymes and suggested a major role for c-Src and tyrosine phosphorylation in mediating normal cell behaviours. For example, c-Src has been implicated in such diverse cell functions as platelet aggregation, cell cycle control and cell motility. The diversity of cellular functions of tyrosine kinases was further indicated by early observations that both the epidermal growth factor (EGF) receptor, important in epithelial cell growth, and the insulin receptor, a key component in metabolic regulation, are tyrosine kinases. Another tyrosine kinase receptor, called Sevenless for its role in determining cell fate of a particular cell type, was found to be necessary for normal eye development in the fruit fly (Drosophila). These and many other discoveries have demonstrated the critical role that the tyrosine kinases and tyrosine phosphorylation play in normal cell regulation and communication and in developmental biology.

Evolutionarily, tyrosine kinases are primarily, if not exclusively, a product of eukaryotic cells. The emergence of protein tyrosine kinases with the appearance of multicellular

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