The long-term goal of this proposal is to determine how the function of two major classes of adhesion receptors, integrins and cadherins, is coordinated during salivary gland development. Integrins link cells to the extracellular matrix, while cadherins mediate intercellular adhesion. At their intracellular domains, both types of receptors. form dynamic multiprotein complexes that connect them to the actin cytoskeleton. Through the formation of these complexes, integrins and cadherins regulate cell attachment and polarity and transmit signals between the cells and their environment. Increasing evidence suggests that integrins and cadherins must be coordinately regulated to mediate cellular interactions essential for development. Our recent in vivo studies indicate that alpha3beta1, a receptor for laminin, affects E-cadherin recruitment to cell-cell junctions during the embryonic development of mouse submandibular gland (SMG). In the absence of alpha3beta1 integrin, E cadherin expression at cell-cell borders is augmented, the organization and distribution of the actin cytoskeleton is altered, and the expression and membrane recruitment of Cdc42 and RhoA, two Rho GTPases known to regulate the organization of the actin cytoskeleton, is switched. Our hypothesis is that SMG development requires coordination of alpha3beta1 integrin and E-cadherin activities, mediated by signaling molecules and the actin cytoskeleton. . To test our hypothesis we propose an integrated set of experimental approaches aimed at elucidating the mechanism via which alpha3beta1 affects E-cadherin function in the developing mouse SMG.
Three specific aims are proposed: 1) determining whether alpha3beta1 integrin regulates the composition of cadherin-associated protein complexes, tyrosine phosphorylation of catenins and interaction of E- cadherin protein complexes with the actin cytoskeleton; 2) determining if signaling via Cdc42 and RhoA mediates E-cadherin recruitment to adherens junctions; and 3) validating the in vivo significance of alpha3beta1 integrin effects on E-cadherin function in transgenic mice expressing mutant forms of the candidate signaling molecules in the SMG.
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