To C or not to C: direct and indirect redox regulation of Src protein tyrosine kinase.
Src protein tyrosine kinase is a master regulator of cell proliferation by modulating cell metabolism, division, survival and migration, thus the mechanisms that regulate Src function are of great interest to cancer research. One emerging mode of Src regulation is its response to reactive oxygen species (ROS). ROS have historically been viewed as damaging agents in cells under oxidative stress, but recent studies establish H(2)O(2) as a secondary messenger to growth signals. A large number of cellular events respond to ROS, and many responses require the activity of Src, suggesting that Src may be a primary target of ROS. How Src kinase responds to ROS has not been established, as conflicting reports of Src activation or inactivation in response to increased concentration of ROS in the cells have been published. To determine how Src directly responds to oxidation, we investigated the effect of the redox environment on purified Src enzyme in vitro. The study reveals that Src is active in the reducing environment, and retains only 8-25% of activity in the absence of reducing agents. The inactivation is mediated by oxidation of Cys277, which leads to Src homodimers linked by a disulfide bond between the Cys277 residues of two Src monomers. A similar inactivation mechanism appears to be conserved in eight of more than 90 PTKs, including three Src family kinases and all four members of the FGFR family. The finding contradicts the view that Src is activated by oxidation, and suggests a complex response by Src to redox regulation. In this Extra View, we examine the conflicting observations in the context of complex mechanisms of Src regulation.
Sun
Gongqin
G
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA. gsun@uri.edu
Kemble
David J
DJ
D000818:Animals; D006801:Humans; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D017382:Reactive Oxygen Species; D019061:src-Family Kinases