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Tight junctions ( z onulae o ccludens) are critical to the maintenance of cell polarity and intracellular barriers between epithelial and endothelial cells. Protein components of the tight junctions include actin filaments, symplekin, occludin, Rab3B, AF-6, 7H6, ZO-1, and ZO-2. Analysis of ZO-1 and -2 resulted in their inclusion in the MAGUK protein family. This family also includes the discs large tumor suppressor protein (Dlg-A) of Drosophila ; p55, an erythrocyte membrane protein; and PSD-95/SAP90, a synaptic membrane protein. All family members contain a region homologous to guanylate kinase (GuK), a src homology (SH3) domain, and multiple PDZ domains. Through these elements, MAGUK proteins function in signal transduction and, possibly, tumor suppression. ZO-1 is a peripheral membrane phosphoprotein that binds to other tight junction proteins such as occludin and AF-6. Via its SH3 domain, ZO-1 interacts with a serine protein kinase that phosphorylates a region immediately C-terminal of the SH3 domain. Taken together, these data indicate that ZO-1 is a critical element in the formation of tight junctions and may also serve an important role in signaling and tumor suppression.