Dlg5 maintains apical aPKC and regulates progenitor differentiation during lung morphogenesis

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle WA 98109, USA. Electronic address: .
Developmental Biology (Impact Factor: 3.55). 03/2013; 377(2). DOI: 10.1016/j.ydbio.2013.02.019
Source: PubMed


Cell polarity plays an important role in tissue morphogenesis; however, the mechanisms of polarity and their role in mammalian development are still poorly understood. We show here that membrane-associated guanylate kinase protein Dlg5 is required for proper branching morphogenesis and progenitor differentiation in mammalian lung. We found that during lung development Dlg5 functions as an apical-basal polarity protein, which is necessary for the apical maintenance of atypical protein kinase C (aPKC). These results identify Dlg5 as a regulator of apical polarity complexes and uncover the critical function of Dlg5 in branching morphogenesis and differentiation of lung progenitor cells.

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    • "Although there does not appear to be any examples of DLG5 in the direct regulation of GPCRs, DLG5 has been implicated in regulating synaptogenesis by enhancing the membrane localization of the transmembrane protein N-cadherin (Wang et al., 2014). DLG5 has also been demonstrated to scaffold atypical protein kinase C (PKC) isoforms, and this provides a mechanism by which DLG5 contributes to the regulation of GPCR-mediated signaling (Nechiporuk et al., 2013). "
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    ABSTRACT: G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are the therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signalling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins (GIPs), PDZ domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role at regulating receptor and channel protein localization of synapses and tight junctions and function to scaffold intracellular signalling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs, and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membrane-associated guanylate-like kinases (MAGUKs) (PSD-95, SAP97, PSD-93, SAP102, DLG5, CARMA3, MPP3, CASK, MAGI-1, MAGI-2, MAGI-3), NHERF proteins (NHERF1, NHERF2, PDZK1, PDZK2), Golgi-associated PDZ proteins (GIPC and CAL), PDZ-GEFs (PDZ-GEF1 and PDZ-GEF2), RGS-Homology-RhoGEFs (PDZ-RhoGEF and LARG), RGS3 and RGS12, spinophilin and neurabin-1, Shank proteins (Shank1, Shank2, Shank3), Par3 and Par6, MUPP1, Tamalin, nNOS, PICK1, and SNX27. The American Society for Pharmacology and Experimental Therapeutics.
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    • "ownloaded from ability to generate Gli repressor primarily from proteo - lytic processing of Gli3 in a Hh - regulated manner thus suffices to supply a substantial proportion of the Hh - mediated patterning activity required for embryonic de - velopment . It is worth noting in this context that Dlg5 À / À animals display defects in lung branching ( Nechiporuk et al . 2013 ) very much like those associated with genetic defects in Hh signaling ( Bellusci et al . 1997 ; Pepicelli et al . 1998 ; Miller et al . 2004 ) . In addition , Dlg5 single - nucle - otide polymorphisms ( SNPs ) have been identified in numerous families of European descent with inflamma - tory bowel disease ( IBD ) ( Friedrichs and Stoll"
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    ABSTRACT: Binding of the Hedgehog (Hh) protein signal to its receptor, Patched, induces accumulation of the seven-pass transmembrane protein Smoothened (Smo) within the primary cilium and of the zinc finger transcription factor Gli2 at the ciliary tip, resulting ultimately in Gli-mediated changes in nuclear gene expression. However, the mechanism by which pathway activation is communicated from Smo to Gli2 is not known. In an effort to elucidate this mechanism, we identified Dlg5 (Discs large, homolog 5) in a biochemical screen for proteins that preferentially interact with activated Smo. We found that disruption of Smo-Dlg5 interactions or depletion of endogenous Dlg5 leads to diminished Hh pathway response without a significant impact on Smo ciliary accumulation. We also found that Dlg5 is localized at the basal body, where it associates with another pathway component, Kif7. We show that Dlg5 is required for Hh-induced enrichment of Kif7 and Gli2 at the tip of the cilium but is dispensable for Gpr161 exit from the cilium and the consequent suppression of Gli3 processing into its repressor form. Our findings suggest a bifurcation of Smo activity in Hh response, with a Dlg5-independent arm for suppression of Gli repressor formation and a second arm involving Smo interaction with Dlg5 for Gli activation. © 2015 Chong et al.; Published by Cold Spring Harbor Laboratory Press.
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    • "ZO1 interacts with ZO2 and ZO3 via their PDZ2 domains to form a tight junctional complex. DLG5 participates in regulation of cell polarity by promoting the apical localization of aPKC 31. It has been found that aPKC and ZO1 are mislocalized, while PAR3 and remains apically localized in DLG5 knockout mice 22, 31. "
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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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