THE TIGHT JUNCTION PROTEIN ZO-1 IS HOMOLOGOUS TO THE DROSOPHILA DISKS-LARGE TUMOR-SUPPRESSOR PROTEIN OF SEPTATE JUNCTIONS

Tight junctions form an intercellular barrier between epithelial cells , serve to separate tissue compartments, and maintain cellular polarit y. Paracellular sealing properties vary among cell types and are regul ated by undefined mechanisms. Sequence of the full-length cDNA for hum an ZO-1, the first identified tight junction component, predicts a pro tein of 1736 aa. The N-terminal 793 aa are homologous to the product o f the lethal(1)discs-large-1 (dlg) tumor suppressor gene of Drosophila , located in septate junctions, and to a 95-kDa protein located in the postsynaptic densities of rat brain, PSD-95. All three proteins conta in both a src homology region 3 (SH3 domain), previously identified in membrane proteins involved in signal transduction, and a region homol ogous to guanylate kinase. ZO-1 contains an additional 943-aa C-termin al domain that is proline-rich (14.1%) and contains an alternatively s pliced domain, whose expression was previously shown to correlate with variable properties of tight junctions. dlg mutations result in loss of apical-basolateral epithelial cell polarity and in neoplastic growt h. These results suggest a protein family specialized for signal trans duction on the cytoplasmic surface of intercellular junctions. These r esults also provide biochemical evidence for similarity between invert ebrate septate and vertebrate tight junctions. The C-terminal domain o f ZO-1, and its alternatively spliced region, appears to confer variab le properties unique to tight junctions.