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  • Title: Protein kinase Cdelta-mediated phosphorylation of alpha6beta4 is associated with reduced integrin localization to the hemidesmosome and decreased keratinocyte attachment.
    Author: Alt A, Ohba M, Li L, Gartsbein M, Belanger A, Denning MF, Kuroki T, Yuspa SH, Tennenbaum T.
    Journal: Cancer Res; 2001 Jun 01; 61(11):4591-8. PubMed ID: 11389095.
    Abstract:
    In mammalian epidermis, expression of the alpha6beta4 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 alpha6beta4 expression and detachment of keratinocytes from the basement membrane. Neoplastic keratinocytes delay maturation, proliferate suprabasally, and retain the expression of the alpha6beta4 integrin in suprabasal cells disassociated from the hemidesmosomes. We now show that the alpha6beta4 integrin is a substrate for serine phosphorylation by protein kinase C in keratinocytes. Furthermore, protein kinase C-mediated phosphorylation of alpha6beta4 is associated with redistribution of this integrin from the hemidesmosome to the cytosol. Specifically, in vitro kinase assays identified the protein kinase Cdelta as the primary isoform phosphorylating alpha6 and beta4 integrin subunits. Using recombinant protein kinase C adenoviruses, overexpression of protein kinase Cdelta but not protein kinase Calpha in primary keratinocytes increased beta4 serine phosphorylation, decreased alpha6beta4 localization to the hemidesmosome complexes, and reduced keratinocyte attachment. Taken together, these results establish a link between protein kinase Cdelta-mediated serine phosphorylation of alpha6beta4 integrin and its effects on alpha6beta4 subcellular localization and keratinocyte attachment to the laminin underlying matrix.
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