The cadherin-catenin adhesion system in signaling and cancer

To assemble into organized tissues, cells must interact with one another and with the extracellular matrix. Cell-cell adhesion is initiated and maintained by adherens junctions. Within these junctions, transmembrane cadherins bind homophilically to join n eighboring cells. Changes in cell adhesion and in the connection of cadherins to the actin cytoskeleton allow cells to carry out the complex events of embryonic development, tissue remodeling, and wound repair. During tumor suppression to malignancy, the aberrant loss of expression of epithelial cadherin is widely believed to mediate transition to metastasis. The catenin p120 is a member of a growing family of armadillo-domain proteins found at cell junctions and in nuclei. P120ctn regulates cell-cell adh esion through its interaction with the highly conserved juxtamembrane domain of classical cadherins. Our group has recently been a pioneer in discovering (Krastad et al., PNAS 2004 and Krastad et al., manuscript) a novel link between the catenin p120 and a protein involved in signaling through cell surface receptors. This protein belongs to the family of heterotrimeric G proteins, G12. Our results have opened a new avenue on the field of cell adhesion since it postulates a model of how signaling proteins could affect cadherin-cadherin interaction between cells. After the initial description of the interaction between p120 and G12, the question is raised now of how this interaction can regulate cadherin function and maintain adhesion. We need to know by wh at mechanisms does G12 regulate p120 function and how this interaction affects the stability of cadherins. Does this interaction influence the lose of adhesion and therefore the transition to metastasis?. By addressing these relevant questions the project proposed not only will investigate the basic mechanisms of cell adhesion but they will also be directly relevant for our comprehension of the transition of epithelial cell adhesion to metastasis.