Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity

Candice E. Paulsen, Thu H. Truong, Francisco J. Garcia, Arne Homann, Vinayak Gupta, Stephen E. Leonard, Kate S. Carroll

Research output: Contribution to journalArticlepeer-review

377 Scopus citations

Abstract

Protein sulfenylation is a post-translational modification of emerging importance in higher eukaryotes. However, investigation of its diverse roles remains challenging, particularly within a native cellular environment. Herein we report the development and application of DYn-2, a new chemoselective probe for detecting sulfenylated proteins in human cells. These studies show that epidermal growth factor receptorg-mediated signaling results in H 2 O 2 production and oxidation of downstream proteins. In addition, we demonstrate that DYn-2 has the ability to detect differences in sulfenylation rates within the cell, which are associated with differences in target protein localization. We also show that the direct modification of epidermal growth factor receptor by H 2 O 2 at a critical active site cysteine (Cys797) enhances its tyrosine kinase activity. Collectively, our findings reveal sulfenylation as a global signaling mechanism that is akin to phosphorylation and has regulatory implications for other receptor tyrosine kinases and irreversible inhibitors that target oxidant-sensitive cysteines in proteins.

Original languageEnglish (US)
Pages (from-to)57-64
Number of pages8
JournalNature Chemical Biology
Volume8
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Bibliographical note

Funding Information:
The authors acknowledge funding from the Camille Henry Dreyfus Teacher Scholar Award (to K.S.C.) and the American Heart Association Scientist Development Award (0835419N to K.S.C.). The authors also wish to thank R. Petter for helpful discussions.

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