Loss of cell:cell contact and acquisition of a motile phenotype are integral components of normal physiological processes including embryonic morphogenesis and wound reepithelialization as well as pathological conditions such as tumor cell invasion. Desmosomes have been reported to disappear during epithelial/mesenchymal transition (EMT) and during keratinocyte migration associated with wound repair. The mechanisms underlying desmosome disappearance and reappearance, and regulatory factors that control these processes are largely unknown; however, ligands for receptor tyrosine kinases are likely candidates. Our hypothesis is that growth factors which directly promote keratinocyte migration also play a role in regulating desmosome disassembly and altered cell:cell adhesion. Our goal is to more clearly define how receptor tyrosine kinases might mediate these responses. During biological processes involving epithelial cell migration and loss of cell:cell adhesion, migration and loss of cell:cell adhesion may occur concomitantly but may involve multiple signaling pathways that could include both immediate and long term consequences of receptor tyrosine kinase activation. This proposal will specifically address l) the distribution of desmosomal cadherins and their associated proteins in growth factor stimulated human keratinocytes, 2) identify and functionally characterize potential growth factor dependent phosphorylation sites of desmosomal proteins and 3) examine downstream consequences of growth factor receptor activation which could directly affect desmosomal cadherin function including alterations in gene expression, protein synthesis or processing by proteinases. These findings should be relevant to our understanding of biological mechanisms involved in both normal and pathological cellular processes where growth factor modulation of epithelial cell migration is observed.
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