The junction-associated protein, zonula occludens-1, localizes to the nucleus before the maturation and during the remodeling of cell-cell contacts.

Abstract

The junction-associated protein zonula occludens-1 (ZO-1) is a member of a family of membraneassociated guanylate kinase homologues thought to be important in signal transduction at sites of cell-cell contact. We present evidence that under certain conditions of cell growth, ZO-1 can be detected in the nucleus. Two different antibodies against distinct portions of the ZO-1 polypeptide reveal nuclear staining in subconfluent, but not confluent, cell cultures. An exogenously expressed, epitope-tagged ZO-1 can also be detected in the nuclei of transfected cells. Nuclear accumulation can be stimulated at sites of wounding in cultured epithelial cells, and immunoperoxidase detection of ZO-1 in tissue sections of intestinal epithelial cells reveals nuclear labeling only along the outer tip of the villus. These results suggest that the nuclear localization of ZO-1 is inversely related to the extent and/or maturity of cell contact.Since cell-cell contacts are specialized sites for signaling pathways implicated in growth and differentiation, we suggest that the nuclear accumulation of ZO-1 may be relevant for its suggested role in membrane-associated guanylate kinase homologue signal transduction.Zonula occludens-1 (ZO-1) is a 210-to 225-kDa peripheral membrane protein of unknown function. It is found associated with the cytoplasmic surfaces of tight junctions (1, 2), cell-cell contacts of cultured nonepithelial brain astrocytes (3), and the intercalated disks (a modified adherens junction) of cardiac myocytes (4). Localization to these structures seems to require established cell-cell contacts, since treatments that prevent the homotypic interaction of E-cadherins (5, 6) or block downstream signaling from this interaction (7) inhibit recruitment of ZO-1 to the margin of cell-cell contact.ZO-1 has recently been identified as a member of a family of putative signaling proteins called membrane-associated guanylate kinase homologues (MAGUKs; ref. 8). The founding member of this family is the product of the lethal (1) discs-large-1 (dlg) tumor suppressor gene of Drosophila (9). Loss-of-function alleles of dlg affect junction formation and result in the overgrowth of imaginal wing disc epithelia, suggesting that this junction associated protein may play a role in epithelial growth control. Other members of this family include: ZO-2, a second tight junction-associated protein (10); PSD-95/SAP-90 and SAP-97, which localize to synaptic junctions (11, 12); p55, which participates in erythrocyte membrane-cytoskeletal interactions (13) tTo whom reprint requests should be addressed at:

Human Alpha-Defensin HNP1 Increases HIV Traversal of the Epithelial Barrier: A Potential Role in STI-Mediated Enhancement of HIV Transmission

“…2A), whereas HD5-treated cells maintained their overall tight junctions. HD5 treatment caused internalization of ZO-1, indicative of a decrease in cell-cell contact (12). Similar results were found in defensin-treated polarized cells (Fig.…”

Enteropathogenic Escherichia coli , Shigella flexneri , and Listeria monocytogenes Recruit a Junctional Protein, Zonula Occludens-1, to Actin Tails and Pedestals

“…ZO-1 generally concentrates at tight junctions or spotlike adherens junctions (21,22,50) or in the nucleus of dividing cells (17). It is not usually accumulated within other actin-rich structures such as stress fibers and filopodia.…”

Interaction of the Plasma Membrane Ca2+ Pump 4b/CI with the Ca2+/Calmodulin-dependent Membrane-associated Kinase CASK

“…Depletion of local Ca 2ϩ by PMCA4b in close proximity to CASK may inhibit Ca 2ϩ /calmodulin binding and subsequently inhibit binding to Tbr-1 and/or translocation of CASK or the CASK⅐Tbr-1 complex to the nucleus. By also translocating to the nucleus, CASK invites analogies with the MAGUK family member ZO-1, which translocates from tight junctions to the nucleus in a cell contact-regulated manner, but the mechanisms governing this process are unclear (42).…”