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Protein Kinase C-mediated Phosphorylation of 6ß4 Is Associated with Reduced Integrin Localization to the Hemidesmosome and Decreased Keratinocyte Attachment¹

Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel 52900 [A. A., M. G., T. T.]; Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, Maryland 20892 [L. L., A. B., M. F. D., S. H. Y.]; and Institute of Molecular Oncology, Showa University, Tokyo 142-8555, Japan [M. O., T. K.]

In mammalian epidermis, expression of the 6ß4 integrin is restricted to the hemidesmosome complexes, which connect the proliferative basal cell layer with the underlying basement membrane. Keratinocyte differentiation is associated with down-regulation of 6ß4 expression and detachment of keratinocytes from the basement membrane. Neoplastic keratinocytes delay maturation, proliferate suprabasally, and retain the expression of the 6ß4 integrin in suprabasal cells disassociated from the hemidesmosomes. We now show that the 6ß4 integrin is a substrate for serine phosphorylation by protein kinase C in keratinocytes. Furthermore, protein kinase C-mediated phosphorylation of 6ß4 is associated with redistribution of this integrin from the hemidesmosome to the cytosol. Specifically, in vitro kinase assays identified the protein kinase C as the primary isoform phosphorylating 6 and ß4 integrin subunits. Using recombinant protein kinase C adenoviruses, overexpression of protein kinase C but not protein kinase C in primary keratinocytes increased ß4 serine phosphorylation, decreased 6ß4 localization to the hemidesmosome complexes, and reduced keratinocyte attachment. Taken together, these results establish a link between protein kinase C-mediated serine phosphorylation of 6ß4 integrin and its effects on 6ß4 subcellular localization and keratinocyte attachment to the laminin underlying matrix.

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