Virus- and cell-encoded tyrosine protein kinases inactivate DNA topoisomerases in vitro.
Tyrosine protein kinase activity is associated with at least eight different retrovirus-encoded onc gene products and with cell receptors for epidermal growth factor, platelet-derived growth factor, tumour growth factor and insulin. Both the onc kinases and the growth factor receptors are membrane proteins whose enzymatic activity has been implicated in stimulation of growth. However, the mechanism by which a signal passes from the plasma membrane to the nucleus to initiate growth remains unknown. As DNA topoisomerases catalyse the interconversion of topological isomers of DNA and hence affect DNA replication, transcription and recombination, they may be involved also in stimulation of growth. Several DNA topoisomerases have been shown to form a covalent complex with DNA via a phosphotyrosine linkage. The DNA-protein complex is postulated to be an intermediate in breaking and rejoining of DNA. The aim of the present study was to determine whether tyrosine protein kinases modulate the activity of topoisomerases by phosphorylating the tyrosine residue involved in DNA binding. We report that incubation of Escherichia coli and calf thymus type I DNA topoisomerases with the Rous sarcoma virus transforming gene product, pp60src, and TPK75, a tyrosine protein kinase purified from normal rat liver, results in a 10-fold loss of topoisomerase activity.
D000818:Animals; D002417:Cattle; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D004926:Escherichia coli / Q000201:enzymology; D005796:Genes; D009857:Oncogenes; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases; D013950:Thymus Gland / Q000201:enzymology; D059004:Topoisomerase I Inhibitors; D014443:Tyrosine / Q000378:metabolism
D059004:Topoisomerase I Inhibitors; D014443:Tyrosine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D004264:DNA Topoisomerases, Type I