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J. Biol. Chem., Vol. 281, Issue 37, 27389-27397, September 15, 2006

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Oxidative Inhibition of Receptor-type Protein-tyrosine Phosphatase by Ultraviolet Irradiation Activates Epidermal Growth Factor Receptor in Human Keratinocytes^*

From the Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Ultraviolet (UV) irradiation rapidly increases tyrosine phosphorylation (i.e. activates) of epidermal growth factor receptors (EGFR) in human skin. EGFR-dependent signaling pathways drive increased expression of matrix metalloproteinases, whose actions fragment collagen and elastin fibers, the primary structural protein components in skin connective tissue. Connective tissue fragmentation, which results from chronic exposure to solar UV irradiation, is a major determinant of premature skin aging (photoaging). UV irradiation generates reactive oxygen species, which readily react with conserved cysteine residues in the active site of protein-tyrosine phosphatases (PTP). We report here that EGFR activation by UV irradiation results from oxidative inhibition of receptor type PTP- (RPTP-). RPTP- directly counters intrinsic EGFR tyrosine kinase activity, thereby maintaining EGFR in an inactive state. Reversible, oxidative inactivation of RPTP- activity by UV irradiation shifts the kinase-phosphatase balance in favor of EGFR activation. These data delineate a novel mechanism of EGFR regulation and identify RPTP- as a key molecular target for antioxidant protection against skin aging.

Received for publication, March 13, 2006 , and in revised form, July 11, 2006.

^* This work was supported in part by National Institutes of Health Grant 1R01ES012920 (to G. J. F.) and a Babcock Endowment. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medical Science I, Rm. 6447, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0609. Tel.: 734-763-1469; Fax: 734-647-0076; E-mail: dianemch{at}umich.edu.

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