Fig. 6. Multiprotein-complexes at TJs. Three major multiprotein complexes are located at TJs. The ZO-1-ZO-2-ZO-3 complex is associated with occludin, claudins and JAMs through multiple interactions. ZO-1 directly associates with all three integral membrane proteins at TJs, i.e. occludin, claudins and JAMs. ZO-2 and ZO-3 directly associate with ZO-1. Both ZO-2 and ZO-3 can also be directly targeted to the plasma membrane by a direct association with occludin and claudins. The PAR-3-aPKC-PAR-6 complex is targeted to the plasma membrane through the interaction of PAR-3 with JAMs. The active form of Cdc42 can associate with the complex by binding to PAR-6, leading to the activation of aPKC. The Pals1-PATJ complex is associated with the membrane through Pals1 binding to CRB1 and CRB3. PATJ associates with Pals1 through its N-terminal MAGUK recruitment (MRE) domain that binds to the L27N domain of Pals1. It also associates with ZO-3 and claudin-1 through PDZ domains. CRB1 and CRB3, similar to the Drosophila orthologue Crumbs, are both localized at the apical surface of epithelial cells but are concentrated at TJs. These three protein complexes might exist independently, but they could also be physically linked. For instance, the Pals1-PATJ complex could be linked to the ZO-1-ZO-2-ZO-3-complex through PATJ binding to ZO-3. In addition, Pals-1 can directly associate with PAR-6 providing a link between the Pals1-PATJ and the PAR-3-aPKC-PAR-6 complexes. Genetic evidence from studies in Drosophila suggests that these protein complexes are also functionally linked in the regulation of epithelial cell polarization (Tanentzapf and Tepass, 2003; Bilder et al., 2003).