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6 Oncogene Products in the Cytoplasm: The Protein Kinases

Tony Hunter


The dogma emerging from the study of prokaryotic regulatory systems in the 1960s led many investigators to suspect that the majority of mammalian oncoproteins would function in the nucleus where they would perturb gene expression and thus induce the transformed phenotype. When it was proved in the mid-1970s that the papovavirus nuclear T antigens were indeed the virally encoded transforming proteins, this surmise appeared to be borne out. The mold was soon broken, however, with the demonstration in 1978 that the transforming protein of Rous sarcoma virus, pp60v-src, was a Cytoplasmic protein. In the ensuing years, a surprisingly large proportion of oncoproteins have been found to act in the cytoplasm.

What do we know about the Cytoplasmic oncogene products? A seminal discovery here was that pp60v-src had an associated protein kinase activity that could transfer phosphate from the γ position of ATP to protein (Collett and Erikson 1978; Levinson et al. 1978). This revelation was exciting because there were many precedents for protein phosphorylation changing the activity of proteins. For instance, phosphorylation of glycogen phosphorylase by phosphorylase kinase increases its activity severalfold. Thus, it appeared that pp60v-src could transform cells through the unregulated phosphorylation of cellular proteins whose activity would be changed upon phosphorylation. Since most protein kinases are pleiotropic, one would anticipate that pp60v-src would be able to phosphorylate many distinct target proteins, altering the activity of each one. In this way, the multifaceted nature of the transformed phenotype could be explained by the existence of target...

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