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J. Biol. Chem., Vol. 280, Issue 48, 40355-40363, December 2, 2005

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Mechanisms of Plakoglobin-dependent Adhesion

DESMOSOME-SPECIFIC FUNCTIONS IN ASSEMBLY AND REGULATION BY EPIDERMAL GROWTH FACTOR RECEPTOR^*

Taofei Yin, Spiro Getsios, Reto Caldelari, Lisa M. Godsel, Andrew P. Kowalczyk¶, Eliane J. Müller||, and Kathleen J. Green1

From the Departments of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, CELLnTEC Advanced Cell Systems AG, 122 Länggass-Strasse, Postfach, Bern CH-3001, Switzerland, the ^¶Departments of Dermatology and Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, and the ^||Institute of Animal Pathology, University of Bern, 122 Länggass-Strasse, Postfach, Bern CH-3001, Switzerland

Plakoglobin (PG) is a member of the Armadillo family of adhesion/signaling proteins that can be incorporated into both adherens junctions and desmosomes. Loss of PG results in defects in the mechanical integrity of heart and skin and decreased adhesive strength in keratinocyte cultures established from the skin of PG knock-out (PG^-/-) mice, the latter of which cannot be compensated for by overexpressing the closely related -catenin. In this study, we examined the mechanisms of PG-regulated adhesion in murine keratinocytes. Biochemical and morphological analyses indicated that junctional incorporation of desmosomal, but not adherens junction, components was impaired in PG^-/- cells compared with PG^+/- controls. Re-expression of PG, but not -catenin, in PG^-/- cells largely reversed these effects, indicating a key role for PG in desmosome assembly. Epidermal growth factor (EGF) receptor activation resulted in Tyr phosphorylation of PG, which was accompanied by a loss of desmoplakin from desmosomes and decreased adhesive strength following 18-h EGF treatment. Importantly, introduction of a phosphorylation-deficient PG mutant into PG null cells prevented the EGF receptor-dependent loss of desmoplakin from junctions, attenuating the effects of long term EGF treatment on cell adhesion. Therefore, PG is essential for maintaining and regulating adhesive strength in keratinocytes largely through its contributions to desmosome assembly and structure. As a target for modulation by EGF, regulation of PG-dependent adhesion may play an important role during wound healing and tumor metastasis.

Received for publication, June 20, 2005 , and in revised form, August 29, 2005.

^* This work was supported by National Institutes of Health Grants R01AR41836, R01AR43380, and Project 4 of P01 DE12328 and the Joseph L. Mayberry endowment (to K. J. G.), National Institutes of Health Grant R01AR048266 (to A. P. K.), and Swiss National Science Foundation Grant 31-59456.99 (to E. J. M.). 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 Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave., Chicago, IL 60611. Tel.: 312-503-5300; Fax: 312-503-8249; E-mail: kgreen{at}northwestern.edu.

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