DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2. Kwan J et al. (2017) Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5(-/-) tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.////////////////// Mutations of the 'discs large' (dlg) tumor suppressor locus in Drosophila lead to imaginal disc neoplasia and a prolonged larval period followed by death. Drosophila dlg and related proteins form a subfamily of the membrane-associated guanylate kinase (MAGUK) protein family and are important components of specialized cell junctions.
NCBI Summary:
This gene encodes a member of the family of discs large (DLG) homologs, a subset of the membrane-associated guanylate kinase (MAGUK) superfamily. The MAGUK proteins are composed of a catalytically inactive guanylate kinase domain, in addition to PDZ and SH3 domains, and are thought to function as scaffolding molecules at sites of cell-cell contact. The protein encoded by this gene localizes to the plasma membrane and cytoplasm, and interacts with components of adherens junctions and the cytoskeleton. It is proposed to function in the transmission of extracellular signals to the cytoskeleton and in the maintenance of epithelial cell structure. Alternative splice variants have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]
General function
Enzyme
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Cellular localization
Plasma membrane
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Ovarian function
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Expression regulated by
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Ovarian localization
Oocyte, Granulosa
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Huang JH, et al 2003 reported the expression of Drosophila neoplastic tumor suppressor genes discslarge, scribble, and lethal giant larvae in the mammalian ovary.
The similarities and differences in molecular mechanisms regulating invertebrate and mammalian folliculogenesis are starting to be deciphered. In Drosophila, the neoplastic tumor suppressor gene discslarge is crucial for suppressing proliferation and movement of follicle cells relative to the growing oocyte. Lethal giant larvae and scribble play similar roles and have been suggested to collaborate intimately with discslarge. The authors have identified and determined the expression pattern of murine homologs of these Drosophila genes. In situ data shows that murine discslarge-1, discslarge-3, discslarge-4, lethal giant larvae, and scribble are expressed in both overlapping and distinct patterns in oocytes and granulosa cells in maturing follicles. Disclarge-4 is expressed in the surface epithelium and is lost in mouse carcinogenic surface epithelial cells. All of these genes, as well as discslarge-2 and discslarge-5, are expressed in human ovaries. The data suggests that as in Drosophila, these tumor suppressors may cooperate during mammalian folliculogenesis, but also have distinct functions.