Volume 272, Number 41, Issue of October 10, 1997 pp. 25429-25432
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
The Activated Form of the Lck Tyrosine Protein Kinase in Cells Exposed to Hydrogen Peroxide Is Phosphorylated at Both Tyr-394 and Tyr-505

(Received for publication, July 24, 1997, and in revised form, August 18, 1997)

James S. Hardwick ^§ and Bartholomew M. Sefton

From the  Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies and the ^§ Department of Biology, University of California at San Diego, La Jolla, California 92037

Members of the Src family of non-receptor tyrosine protein kinases are known to be inhibited by the intramolecular association between a phosphorylated carboxyl-terminal tyrosine residue and the SH2 domain. We have previously shown that exposure of cells to H₂O₂ strongly activates Lck, a lymphocyte-specific Src family kinase, by inducing phosphorylation on Tyr-394, an absolutely conserved residue within the activation loop of the catalytic domain. Here we show that Lck that has been activated by H₂O₂ is simultaneously phosphorylated at both the carboxyl-terminal tyrosine (Tyr-505) and Tyr-394. Thus, dephosphorylation of Tyr-505 is not a prerequisite for either phosphorylation of Lck at Tyr-394 or catalytic activation of the kinase. These results indicate that activation of Lck by phosphorylation of Tyr-394 is dominant over any inhibition induced by phosphorylation of Tyr-505. We propose that these results may be extended to all Src family members.

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