Sci. STKE, 26 July 2005
REACTIVE OXYGEN SPECIES Redox Regulation of Src
Giannoni et al. present evidence for a new layer of regulation of the tyrosine kinase Src in adherent cells. The activity of Src is controlled by phosphorylation events, but Giannoni et al. suggest that oxidation may also have an important role. They used the reagent BIAM, N-(biotinoyl)-N'-(iodoacetyl)ethylenediamine, to detect oxidized proteins in cells undergoing oxidative stress from exposure to glucose oxidase. Binding of integrins to fibronectin in the extracellular matrix causes generation of reactive oxygen species (ROS) in cells. The authors used the above technique and others to also show oxidation of cysteine residues on Src in 3T3 cells plated on fibronectin. The oxidation correlated with activation of the kinase (as monitored by autophosphorylation), and treatment of cells with nordihydroguaiaretic acid (NDGA) to prevent generation of ROS inhibited the increase in kinase activity. They used mutagenesis of conserved cysteine residues to identify the particular cysteines that were modified and showed that mutants lacking the two key cysteines were not oxidized and were not activated in cells adhering to fibronectin. Src is a protooncogene, and overexpression of an oncogenic mutant of Src in cultured cells caused transformation. However, the addition of the cysteine mutants to prevent oxidation inhibited the capacity of the oncogenic protein to transform cells in culture. The authors propose that redox regulation of Src, along with its better known regulation by phosphorylation, may modulate the many effects of the kinase in normal and cancerous cells.
E. Giannoni, F. Buricchi, G. Raugei, G. Ramponi, P. Chiarugi, Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol. Cell. Biol. 25, 6391-6403 (2005). [Abstract] [Full Text]
Citation: Redox Regulation of Src. Sci. STKE 2005, tw269 (2005).
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