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J. Biol. Chem. 280 (25): 23918-23925

© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Inactivation of Src Family Tyrosine Kinases by Reactive Oxygen Species in Vivo*

Hua Tang{ddagger}§, Qin Hao{ddagger}, Stacey A. Rutherford{ddagger}, Brad Low{ddagger}, , and Z. Joe Zhao

Department of Biochemistry, The University of Texas Health Center at Tyler, Tyler, Texas 75708 and the Division of Hematology/Oncology, Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232

Abstract: Reactive oxygen species, including H2 O2, Formula and Formula are constantly produced in the human body and are involved in the development of cardiovascular diseases. Emerging evidence suggests that reactive oxygen species, besides their deleterious effects at high concentrations, may be protective. However, the mechanism underlying the protective effects of reactive oxygen species is not clear. Here, we reported a novel finding that H2O2 at low to moderate concentrations (50-250 μM) markedly inactivated Src family tyrosine kinases temporally and spatially in vivo but not in vitro. We further showed that Src family kinases localized to focal adhesions and the plasma membrane were rapidly and permanently inactivated by H2O2, which resulted from a profound reduction in phosphorylation of the conserved tyrosine residue at the activation loop. Interestingly, the cytoplasmic Src family kinases were activated gradually by H2O2, which partially compensated for the loss of total activities of Src family kinases but not their functions. Finally, H2O2 rendered endothelial cells resistant to growth factors and cytokines and protected the cells from inflammatory activation. Because Src family kinases play key roles in cell signaling, the rapid inactivation of Src family kinases by H2 O2 may represent a novel mechanism for the protective effects of reactive oxygen species.

Received for publication March 30, 2005.

§ To whom correspondence should be addressed: Dept. of Biochemistry, The University of Texas Health Center at Tyler, 11937 U. S. Highway 271, Tyler, TX 75708. Tel.: 903-877-7938; Fax: 903-877-2881; E-mail: hua.tang{at}

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