Integrins are heterodimeric cell surface receptors for the extracellular matrix (ECM). In epithelial ceils they serve to adhere the basal surface of the cell to the basement membrane; α3β1 integrin is a receptor for laminin, a major component of basement membranes. Our studies have identified novel roles for α3β1 integrin. In addition to being present on the basal surface of cells, α3β1 integrin is also found at lateral cell membranes, a location inconsistent with its function as a receptor for the ECM. We have now demonstrated that α3β1 integrin is also a component of the cadherin:catenin complex, and that the interaction of α3β1 with CD151, a member of the tetraspanin family, is required to stimulate cadherin-mediated cell-cell adhesion. We now propose to examine the significance of the integrin:tetraspanin interaction in vivo during development. Toward this end we have derived a conditional mutation of the α3 integrin gene and we are now breeding these mice with several Cre recombinase-expressing mice, to study the role of α3β1 integrin in specific cell types during development and tumorigenesis. Specific Aim 1: To study coordinate signaling mediated by α3β1 integrin and associated complexes. Hypothesis: Distinct signaling pathways are activated by alternative and possibly competitive association of α3β1 integrin with the cadherin:catenin complex or with RTKs. Specific Aim 2: To examine the role of integrin-dependent Wnt signaling in epithelial morphogenesis. Specific Aim 3: To determine the requirement for the α3β1 integrin:tetraspanin interaction in cell morphogenesis.
