Willott E, Balda MS, Fanning AS, Jameson B, Van Itallie C, Anderson JM.. The tight junction protein ZO-1 is homologous to the Drosophila discs- large tumor suppressor protein of septate junctions. Proc Natl Acad Sci USA 90: 7834-7838

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/1993; 90(16):7834-8. DOI: 10.1073/pnas.90.16.7834
Source: PubMed


Tight junctions form an intercellular barrier between epithelial cells, serve to separate tissue compartments, and maintain cellular polarity. Paracellular sealing properties vary among cell types and are regulated by undefined mechanisms. Sequence of the full-length cDNA for human ZO-1, the first identified tight junction component, predicts a protein of 1736 aa. The N-terminal 793 aa are homologous to the product of 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 contain both a src homology region 3 (SH3 domain), previously identified in membrane proteins involved in signal transduction, and a region homologous to guanylate kinase. ZO-1 contains an additional 943-aa C-terminal domain that is proline-rich (14.1%) and contains an alternatively spliced 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 growth. These results suggest a protein family specialized for signal transduction on the cytoplasmic surface of intercellular junctions. These results also provide biochemical evidence for similarity between invertebrate septate and vertebrate tight junctions. The C-terminal domain of ZO-1, and its alternatively spliced region, appears to confer variable properties unique to tight junctions.

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    • "The component of the PAR complex, aPKC, is apically localized and participates in maintenance of apical-lateral polarity. aPKC can recruit the PAR3-PAR6 complex from tight junction sites to subapical region; as a result, PAR3 is excluded from tight junction sites, allowing for tight junction formation 28. ZO1, located on the plasma membrane surface at sites of the cell-cell junction 29, is a well-known organizer for tight junction and notable epithelial marker 30. ZO1 interacts with ZO2 and ZO3 via their PDZ2 domains to form a tight junctional complex. "
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    ABSTRACT: Failure in establishment and maintenance of epithelial cell polarity contributes to tumorigenesis. Loss of expression and function of cell polarity proteins is directly related to epithelial cell polarity maintenance. The polarity protein discs large homolog 5 (DLG5) belongs to a family of molecular scaffolding proteins called Membrane Associated Guanylate Kinases (MAGUKs). As the other family members, DLG5 contains the multi-PDZ, SH3 and GUK domains. DLG5 has evolved in the same manner as DLG1 and ZO1, two well-studied MAGUKs proteins. Just like DLG1 and ZO1, DLG5 plays a role in cell migration, cell adhesion, precursor cell division, cell proliferation, epithelial cell polarity maintenance, and transmission of extracellular signals to the membrane and cytoskeleton. Since the roles of DLG5 in inflammatory bowel disease (IBD) and Crohn's disease (CD) have been reviewed, here, our review focuses on the roles of DLG5 in epithelial cell polarity maintenance and cancer development.
    Preview · Article · May 2014 · International journal of biological sciences
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    • "MAGUKs originally referred to a group of cell junction proteins composed of synaptic scaffold protein PSD-95 from mammals, DLG tumour suppressor from Drosophila, and tight junction protein ZO-1 from mammalian epithelia (Cho et al, 1992; Willott et al, 1993; Woods and Bryant, 1993). The family has since grown to encompass a large number of scaffold proteins that play critical roles in diverse cellular processes including inter-cellular connections, cell polarity development and maintenance, synaptic plasticity, and cell survival in multicellular eukaryotes (Funke et al, 2005; Velthuis et al, 2007; Mendoza et al, 2010). "
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    ABSTRACT: Membrane-associated guanylate kinases (MAGUKs) are a large family of scaffold proteins that play essential roles in tissue developments, cell-cell communications, cell polarity control, and cellular signal transductions. Despite extensive studies over the past two decades, the functions of the signature guanylate kinase domain (GK) of MAGUKs are poorly understood. Here we show that the GK domain of DLG1/SAP97 binds to asymmetric cell division regulatory protein LGN in a phosphorylation-dependent manner. The structure of the DLG1 SH3-GK tandem in complex with a phospho-LGN peptide reveals that the GMP-binding site of GK has evolved into a specific pSer/pThr-binding pocket. Residues both N- and C-terminal to the pSer are also critical for the specific binding of the phospho-LGN peptide to GK. We further demonstrate that the previously reported GK domain-mediated interactions of DLGs with other targets, such as GKAP/DLGAP1/SAPAP1 and SPAR, are also phosphorylation dependent. Finally, we provide evidence that other MAGUK GKs also function as phospho-peptide-binding modules. The discovery of the phosphorylation-dependent MAGUK GK/target interactions indicates that MAGUK scaffold-mediated signalling complex organizations are dynamically regulated.
    Full-text · Article · Nov 2011 · The EMBO Journal
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    • "Membrane proteins such as cell adhesion molecules, receptors, and channels form functional clusters within selective subcellular regions by binding to PDZ domains [2-5]. Furthermore, some PDZ proteins also anchor specific cytosolic proteins such as protein kinases, cytoskeleton-regulating enzymes and second-messenger-producing enzymes [2,6], and hence, contribute to precise signal transduction between extracellular and intracellular spaces at specific sites such as postsynaptic densities in neurons [2,7], immunological synapses in T-lymphocytes [8,9] and tight junctions in endothelial and epithelial cells [1,10]. "
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    ABSTRACT: The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level. Here, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high-virulence viral proteins bearing a refined PDZ-binding motif. Our refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction.
    Full-text · Article · Jun 2011 · BMC Genomics
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