BIOCHEMISTRY AND REGULATION OF CADHERIN ACTIVITY

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Cadherins are homophilic cell adhesion proteins important for the organization of cells in tissues. Cadherin adhesion specificity contributes to cell recognition and cell sorting during development. Also, physiological regulation of cadherins at the cell surface plays very important roles in tissue morphogenesis and homeostasis. Indeed, disruption of these regulatory mechanisms for E-cadherin in epithelial tumors contributes to the state of malignancy and metastasis. Several models for the mechanism of cadherin regulation have been proposed, but it is not yet known whether they occur in real tissues or organisms. Cadherins function as homodimers at the cell surface, but the structural basis of dimerization and their assembly into higher order adhesive complexes is not understood. Also, the molecular determinants of the homophilic adhesive bond and the nature of cadherin specificity are still poorly understood. The catenins are proteins that link cadherins to the actin cytoskeleton and control cadherin function in the cell. Recent findings, however, also implicate the juxtamembrane domain of the cytoplasmic tail and the protein p120ctn in cadherin function. The overall objectives of the proposed research are to understand the molecular nature of the cadherin homophilic adhesive bond, the molecular mechanisms that underlie the regulation of cadherin-mediated adhesion, and how such regulatory mechanisms are used to control tissue morphogenesis. The major aims are: 1. Determine the structural properties of the soluble cadherin extracellular segments that underlie the basic homophilic adhesive binding mechanism and binding specificity, using a combination of deletion analysis, functional assays, and biophysical methods. 2. Analyze the roles of p120ctn and the juxtamembrane region compared to the catenin-binding domain and catenins in the basic mechanism and physiological regulation of cadherin-mediated adhesion in Xenopus embryos and cultured cells. 3. Use activating and conformation specific monoclonal antibodies to investigate how inside out signaling controls the homophilic adhesion properties of the cadherin extracellular segment. 4. Ask how spatial and temporal regulation of cadherin-mediated adhesion contributes to the morphogenesis of tissues in the Xenopus embryo. The results from these studies should help improve our understanding of the functions of the cadherins in tissue morphogenesis during embryogenesis and organ homeostasis, in tumor progression, and in morphogenetic defects associated with congenital diseases.