title: Activation of Src family tyrosine kinases by ferric ions.
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 (Tyr(530) 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 Fe(3+) ions with affinities at pH4.0 of 33 and 252μM, and phosphorylation increased the affinities at least 10-fold to 1.4 and 23μM, as measured by absorbance spectroscopy. The corresponding phosphorylated peptide from the SFK Lyn bound two Fe(3+) ions with much higher affinities (1.2pM and 160nM) 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 Fe(3+) ions, a significant enhancement of kinase activity was observed. In contrast Lyn or Hck kinases in the unphosphorylated active state were significantly inhibited by Fe(3+) ions. These results suggest that Fe(3+) ions can regulate SFK activity by binding to the phosphorylated C-terminal regulatory tyrosine.
authors: The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia. Electronic address: grahamsb@unimelb.edu.au.
authors: Graham S
authors: GS
authors: Baldwin
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors: Daisy Sio-Seng
authors: DS
authors: Lio
authors: The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia.
authors: Audrey
authors: A
authors: Ferrand
authors: Ludwig Institute for Cancer Research, Melbourne Branch, Austin Hospital, Heidelberg, Victoria, Australia.
authors: Bruno
authors: B
authors: Catimel
authors: The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia.
authors: B Philip
authors: BP
authors: Shehan
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors: Raymond S
authors: RS
authors: Norton
authors: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
authors: Heung-Chin
authors: HC
authors: Cheng
mesh_terms: D000595:Amino Acid Sequence; D002412:Cations; D004789:Enzyme Activation; D005290:Ferric Compounds / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002412:Cations; D005290:Ferric Compounds; D019061:src-Family Kinases
keywords: Calcium; Ferric; Iron; Kinase; Phosphotyrosine