Members of the G12 subfamily of heterotrimeric G proteins play important roles in cell proliferative and developmental pathways, and have also been implicated in oncogenic transformation. We recently identified a novel interaction between cell surface cadherins and G12 proteins that involves binding of the G protein alpha-subunit to the cytoplasmic domain of specific cell-surface cadherins. The interaction of G12 proteins with cadherin causes the release of the transcriptional activator beta-catenin from cadherin, leading to up-regulated beta-catenin- mediated transcriptional activation. Furthermore, the G12/cadherin interaction negatively regulates the extracellular function of cadherin in promoting cell-cell adhesion and suppressing cell migration. In this application, strategies are detailed for developing molecular tools to dissect the biology of the G12/cadherin interaction. These tools will be utilized in experimental approaches designed to define the importance of the G12/cadherin interaction in beta-catenin-mediated oncogenic transformation, cell adhesion, and metastasis. The role of specific ligands and their corresponding G protein-coupled receptors that impact on G12-mediated signaling will also be examined. An additional focus of the project is to dissect the mechanisms by which interaction of G12 proteins with cadherin disrupts cadherin-mediated adhesion and suppression of cell migration; preliminary evidence has been obtained that G12 proteins regulate these two functions of cadherin through distinct mechanisms. The interrelationships between the G12/cadherin interaction and the interaction of additional proteins with the cytoplasmic domain of cadherin will be investigated to identify proteins involved in the distinct mechanisms of cadherin-mediated adhesion versus the migration suppression associated with cadherin function. Together, these studies should allow elucidation of the role of the G12/cadherin interaction in beta-catenin-mediated signaling, cell adhesion and cell migration, and the potential involvement of aberrant activation of G12 proteins in oncogenesis and the metastatic progression of cancers. In addition, these studies should facilitate the identification and validation of inhibitors of the G12/cadherin interaction as potential lead compounds for the development of anti-proliferative and anti-metastatic drugs.
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