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J. Biol. Chem., Vol. 279, Issue 35, 37191-37200, August 27, 2004

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Epidermal Growth Factor Receptor Inhibition Promotes Desmosome Assembly and Strengthens Intercellular Adhesion in Squamous Cell Carcinoma Cells^*

Jochen H. Lorch¶, Jodi Klessner||**, J. Ken Park||, Spiro Getsios||, Yvonne L. Wu||, M. Sharon Stack, and Kathleen J. Green||¶¶

From the ^||Departments of Pathology and Dermatology, The Robert H. Lurie Cancer Center, the Division of Hematology and Oncology, and the Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611

The epidermal growth factor receptor (EGFR) has been proposed as a key modulator of cadherin-containing intercellular junctions, particularly in tumors that overexpress this tyrosine kinase. Here the EGFR tyrosine kinase inhibitor PKI166 and EGFR blocking antibody C225, both of which are used clinically to treat head and neck cancers, were used to determine the effects of EGFR inhibition on intercellular junction assembly and adhesion in oral squamous cell carcinoma cells. EGFR inhibition resulted in a transition from a fibroblastic morphology to a more epithelial phenotype in cells grown in low calcium; under these conditions cadherin-mediated cell-cell adhesion is normally reduced, and desmosomes are absent. The accumulated levels of desmoglein 2 (Dsg2) and desmocollin 2 increased 1.7-2.0-fold, and both desmosomal cadherin and plaque components were recruited to cell-cell borders. This redistribution was paralleled by an increase in Dsg2 and desmoplakin in the Triton-insoluble cell fraction, suggesting that EGFR blockade promotes desmosome assembly. Importantly, E-cadherin expression and solubility were unchanged. Furthermore, PKI166 blocked tyrosine phosphorylation of Dsg2 and plakoglobin following epidermal growth factor stimulation, whereas no change in phosphorylation was detected for E-cadherin and -catenin. The increase in Dsg2 protein was in part due to the inhibition of matrix metalloproteinase-dependent proteolysis of this desmosomal cadherin. These morphological and biochemical changes were accompanied by an increase in intercellular adhesion based on functional assays at all calcium concentrations tested. Our results suggest that EGFR inhibition promotes desmosome assembly in oral squamous cell carcinoma cells, resulting in increased cell-cell adhesion.

Received for publication, May 7, 2004 , and in revised form, June 8, 2004.

^* This work was supported by National Institutes of Health Grants PO1 DE12328 (Project 4) and RO1 AR41836 (to K. J. G.) and by the J. L. Mayberry 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.

^¶ Present address: Klinik fur Innere Medizin IV, Martin-Luther-University Halle, 06097 Halle, Germany.

^** Supported by National Institutes of Health Training Grant T32 CA80621.

Supported by a postdoctoral fellowship from the Canadian Institutes of Health Research.

^¶¶ To whom correspondence should be addressed: Dept. of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-5300; Fax: 312-503-8240; E-mail: kgreen{at}northwestern.edu.

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