Regulation of cell polarity and tight junction formation in vertebrate epithelial and endothelial cells by cell adhesion receptors

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Until recently, little was known about the molecules regulating the formation of tight junctions (TJ) and membrane polarity in vertebrate epithelial and endothelial cells. The recent discovery of a multicomponent signalling complex consisting of PDZ domain-containing scaffolding proteins (PAR-3, PAR-6) and signal transducing proteins (aPKC, Cdc42) has attracted much attention in the field of cell polarity. This complex is conserved through evolution and seems to be required for the formation and/or maintenance of tight junctions in epithelial cells. With JAM-1 we have identified the first transmembrane component in TJs which associates with PAR-3. Our studies aim at a more detailed understanding of the function of JAM-1 in the formation of TJs. The specific aims are: (1) to analyze if the association of PAR-3 with JAM is required for a) the recruitment of PAR-3 to intercellular contacts and b) the formation of tight junctions in epithelial cells; (2) to analyze protein complexes involving JAMs and members of the ZO family of TJ proteins (ZO-1, ZO-2, and ZO-3); and (3) to analyze if Hepatocyte Growth Factor affects TJ integrity by acting on the TJ localization of JAM-1.