Activation of Src family tyrosine kinases by ferric ions |
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Authors: | Graham S. Baldwin Daisy Sio-Seng Lio Audrey Ferrand Bruno Catimel B. Philip Shehan Raymond S. Norton Heung-Chin Cheng |
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Affiliation: | 1. The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia;2. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia;3. Ludwig Institute for Cancer Research, Melbourne Branch, Austin Hospital, Heidelberg, Victoria, Australia;4. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia |
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Abstract: | The Src-family tyrosine kinases (SFKs) are oncogenic enzymes that contribute to the initiation and progression of many types of cancer. In normal cells, SFKs are kept in an inactive state mainly by phosphorylation of a consensus regulatory tyrosine near the C-terminus (Tyr530 in the SFK c-Src). As recent data indicate that tyrosine modification enhances binding of metal ions, the hypothesis that SFKs might be regulated by metal ions was investigated. The c-Src C-terminal peptide bound two Fe3 + ions with affinities at pH 4.0 of 33 and 252 μM, and phosphorylation increased the affinities at least 10-fold to 1.4 and 23 μM, as measured by absorbance spectroscopy. The corresponding phosphorylated peptide from the SFK Lyn bound two Fe3 + ions with much higher affinities (1.2 pM and 160 nM) than the Src C-terminal peptide. Furthermore, when Lyn or Hck kinases, which had been stabilised in the inactive state by phosphorylation of the C-terminal regulatory tyrosine, were incubated with Fe3 + ions, a significant enhancement of kinase activity was observed. In contrast Lyn or Hck kinases in the unphosphorylated active state were significantly inhibited by Fe3 + ions. These results suggest that Fe3 + ions can regulate SFK activity by binding to the phosphorylated C-terminal regulatory tyrosine. |
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Keywords: | CCK, cholecystokinin CDK2, cyclin-dependent kinase 2 DMEM, Dulbecco's Modified Eagle Medium HBS, HEPES-buffered saline SFK, Src-family tyrosine kinases |
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