Abstract
ZO (zonula occludens) proteins are scaffolding proteins providing the structural basis for the assembly of multiprotein complexes at the cytoplasmic surface of intercellular junctions. In addition, they provide a link between the integral membrane proteins and the filamentous cytoskeleton. ZO proteins belong to the large family of membrane-associated guanylate kinase (MAGUK)-like proteins comprising a number of subfamilies based on domain content and sequence similarity. Besides their structural function at cell-cell contacts, ZO proteins appear to participate in the regulation of cell growth and proliferation. Detailed molecular studies have shown that ZO proteins exhibit conserved functional nuclear localization and nuclear export motifs within their amino acid sequence. Further, ZO proteins interact with dual residency proteins localizing to the plasma membrane and the nucleus. Although the nuclear targeting of ZO proteins has well been described, many questions concerning the biological significance of this process have remained open. This review focuses on the dual role of ZO proteins, being indispensable structural components at the junctional site and functioning in signal transduction pathways related to gene expression and cell behavior.
Highlights
Epithelial and endothelial cells attach to each other by various occluding junctions which rely on the function of specific proteins characterized by common structural features, that is, one or more transmembrane domains flanked by cytoplasmic and extracellular portions
Zonula occludens (ZO) proteins belong to the large family of membrane-associated guanylate kinase (MAGUK)-like proteins comprising a number of subfamilies based on domain content and sequence similarity
This review focuses on the dual role of ZO proteins, being indispensable structural components at the junctional site and functioning in signal transduction pathways related to gene expression and cell behavior
Summary
Epithelial and endothelial cells attach to each other by various occluding junctions which rely on the function of specific proteins characterized by common structural features, that is, one or more transmembrane domains flanked by cytoplasmic and extracellular portions. Accumulating experimental evidence has suggested that protein-protein interactions at the cytoplasmic region(s) of such transmembrane junctional proteins modulate the extracellular action of the protein which accomplishes homophilic or heterophilic binding to extracellular domains of junctional proteins of neighbouring cells In this way, a regulatable intercellular seal is created. ZO proteins interact directly with most of the transmembrane proteins localizing at TJs, such as occludin, claudins, JAM (Junctional adhesion molecule), tricellulin, and CAR (coxsackievirus and adenovirus receptor) [8,9,10,11,12,13,14] (Figure 1) Their association with AJs is accomplished through binding to alpha-catenin [14, 15] and members of the p120 catenin family [14,15,16,17] as well as to the nectin-interacting. ZO proteins interact with a series of cytoplasmic proteins, including adapters, signaling molecules and transcriptional regulators [22,23,24,25,26,27] suggesting a novel function of ZO proteins, far beyond their role as indispensable structural components at the junction site
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