The extracellular matrix (ECM) and the integrin ECM receptor family appear to play important roles in kidney development although the signaling pathways involved are not fully understood. The long range objectives of this proposal are to determine the importance of adherens junctions and tight junctions in regulation of renal epithelial tubule formation and cell polarity development. They are designed to obtain fundamental information about the cellular mechanisms involved in renal nephron development and kidney diseases which exhibit changes in membrane protein targeting. Renal epithelial cells will be utilized to study the role of integrin-regulated signal transduction pathways in modulation of cell-cell adhesion during epithelial tubule formation. These studies will be concerned with: 1) the role of PI 3-kinase and the proto-oncogene PKB/Akt in the regulation of adherens junction and tight junction function, 2) the role of Rho family GTPases in regulation of cell-cell adhesion, cell migration and organization of the epithelial cytoskeleton, 3) the role of Rho family GTPase signaling pathway downstream effectors Rho-kinase and p21-activated kiriase, myosin H phosphorylation and actin polymerization in regulation of cell migration and cell adhesion during tubule formation, and 4) test the hypothesis that activation of Rho family GTPases play an important role in regulation of signal transduction pathways during during development of polarized epithelial tubules. These events will be analyzed biochemically by SDS-PAGE and immunoblotting, structurally by confocal microscopy and physiologically by measuring tight junction permeability.