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J. Biol. Chem., Vol. 280, Issue 52, 42694-42700, December 30, 2005

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Receptor-type Protein-tyrosine Phosphatase- Regulates Epidermal Growth Factor Receptor Function^*

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

Epidermal growth factor receptor (EGFR), the prototypic receptor protein tyrosine kinase, is a major regulator of growth and survival for many epithelial cell types. We report here that receptor-type protein-tyrosine phosphatase- (RPTP-) dephosphorylates EGFR and thereby regulates its function in human keratinocytes. Protein-tyrosine phosphatase (PTP) inhibitors induced EGFR tyrosine phosphorylation in intact primary human keratinocytes and cell-free membrane preparations. Five highly expressed RPTPs (RPTP-, , , µ, and ) were functionally analyzed in a Chinese hamster ovary (CHO) cell-based expression system. Full-length human EGFR expressed in CHO cells, which lack endogenous EGFR, displayed high basal (i.e. in the absence of ligand) tyrosine phosphorylation. Co-expression of RPTP-, but not other RPTPs, specifically reduced basal EGFR tyrosine phosphorylation. RPTP- also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP- preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. Overexpression of wild-type or catalytically inactive RPTP- reduced or enhanced, respectively, basal and EGF-induced EGFR tyrosine phosphorylation in human keratinocytes. Furthermore, siRNA-mediated knockdown of RPTP- increased basal and EGF-stimulated EGFR tyrosine phosphorylation and augmented downstream Erk activation in human keratinocytes. RPTP- levels increased in keratinocytes as cells reached confluency, and overexpression of RPTP- in subconfluent keratinocytes reduced keratinocyte proliferation. Taken together, the above data indicate that RPTP- is a key regulator of EGFR tyrosine phosphorylation and function in human keratinocytes.

Received for publication, July 15, 2005 , and in revised form, October 28, 2005.

^* This work was supported in part by the 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: Dept. of Dermatology, University of Michigan Medical School, Medical Science I, Rm. 6447, 1150 W. Medical Ctr. Dr., Ann Arbor, MI 48109-0609. Tel.: 734-763-1469; Fax: 734-647-0076; E-mail: dianemch{at}umich.edu.

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