CONTROL OF EPITHELIAL CELL MOTILITY BY E CADHERIN

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DESCRIPTION: (Adapted from the applicant's abstract) - The hypothesis of this revised application is that epithelial cell motility is suppressed by signals generated as a result of E-cadherin mediated cell-cell contact. Published findings from the principal investigator's lab have shown that the catenin binding domain of E-cadherin is required for adhesion, but not for suppression of motility, whereas the JM domain (comprising 30-50 amino acids just next the to plasma membrane) suppresses motility but does not support adhesion in many cell types. Data from a new collaborator, Michael Kinch, indicate that engagement of E-cadherin stimulates the tyrosine phosphorylation of several proteins in breast epithelial cells and MDCK cells. A new specific aim (Aim 1) based on these data is to determine whether this is the case for keratinocytes as well and then determine which parts of the E-cad tail are required to generate this tyrosine phosphorylation response and identify tyrosine-phosphorylated proteins. Aim 2 proposes to identify components that interact with the JM domain of E-cadherin and test their role in suppression of motility. The final aim is to determine the role of the JM domain in regulating the motility of keratinocytes in vitro and in vivo. This will be accomplished first by expressing dominant-negative forms of E-cadherin and N-cadherin in cultured cells, and then using the K14 promoter to target selected dominant-negative constructs to the epidermis of transgenic mice.