STRUCTURE/FUNCTION ANALYSIS OF K CADHERIN

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Cadherins are membrane proteins mediating Ca-dependent homophilic cell adhesion and have been categorized into two major groups based on structural similarities. The prototype of class I cadherins, E- cadherin is expressed in epithelial cells. Its downregulation correlates with tumor metastasis and invasiveness. Class II cadherins comprise a list of almost ten very closely related molecules which lack specific sequences determining homophilic aggregation. High level expression has been documented not only in normal epithelial cells but also in loose tissues, migrating cells and neoplasms. Thus the functions of class H cadherins do not completely overlap with functions assigned to class I cadherins. The proposed study aims to identify the homophilic interface of a class II, fetal kidney-specific cadherin, K-cadherin (KCad), also known as cadherin -6 (cad6), by mutational analysis based on the crystal structure of E- and N- cadherin. A panel of mutants will be scored for their ability to abrogate homophilic interactions in the Drosophila S2 cell line. These data can be extrapolated to other members of the class II subfamily and may provide the molecular basis for the pharmacologic intervention of cadherin function. The ability of secreted forms of these mutants to inhibit kidney development will also be evaluated and these findings will provide necessary information to understand molecular mechanisms underlying the development of other organs which develop through mesenchymal- to-epithelial transitions. Such inductive interactions occur during salivary glands, lungs, hair and tooth development. Moreover, insights into potential role for cell adhesion in aberrant growth will be obtained, since KCad has been documented to be upregulated in various neoplasms, mainly kidney carcinoma.