Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia.

Abstract

Abstract. The Discs large (Dig) protein of Drosophila is the prototypic member of a growing family of proteins termed membrane-associated guanylate k_inase homologs (MAGUKs). The MAGUKs are composed of a series of peptide domains that include one or three DHR/PDZs, an SH3, and a region homologous to guanylate kinase (GUK). We have previously shown that the product of this gene, the Dig protein, is localized at the septate junctions between epithelial cells, and that mutations in the gene cause neoplastic overgrowth of the imaginal discs. The dig locus is therefore defined as a tumor suppressor gene. In this paper, we show that the Dig protein is localized on the cytoplasmic face of the septate junction and is required for the maintenance of this structure. It is also required for proper organization of the cytoskeleton, for the differential localization of membrane proteins, and for apicobasal polarity of epithelial cells. However, these other functions can be uncoupled from Dlg's role as a tumor suppressor since mutations in two domains of the protein, the SH3 and GUK, cause loss of normal cell proliferation control without affecting the other functions of the protein. These results suggest that, besides regulating cellular proliferation, the Dig protein is a critical component of the septate junctions and is required for maintaining apicobasal polarity in Drosophila epithelium.

Phosphorylation of the discs large tumour suppressor protein controls its membrane localisation and enhances its susceptibility to HPV E6-induced degradation

“…The Dlg tumour suppressor is a key regulator of diverse processes including cell polarity control, cell proliferation and cell attachment Woods et al, 1996;Bilder et al, 2000). In addition, recent studies, where exposure to osmotic shock induced an increase in p38g-induced phosphorylation of Dlg (Sabio et al, 2005), have suggested that it may also have a role in the cells' response to changes in the extracellular environment.…”

“…Although all of them appear to be involved in regulating signalling pathways from the cell membrane, most information is available concerning Dlg. In Drosophila, Dlg is classified as a tumour suppressor, regulating processes controlling cell polarity and proliferation (Woods et al, 1996;Bilder et al, 2000). In mice, loss of Dlg function results in craniofacial abnormalities consistent with a breakdown in the normal control of cell polarity (Caruana and Bernstein, 2001).…”

Oncogenic human papillomavirus E6 proteins target the discs large tumour suppressor for proteasome-mediated degradation

“…Epithelia form sheets of polarized cells, with the apical and basolateral sides separated by tight junctions (Kim, 1997), and DLG is requried for the organization of these junctional complexes. Tight junctions form a continuous intercellular contact and their absence is associated with defective cell-cell adhesion, a loss of cell polarity and unregulated proliferation (Anderson, 1996;Woods et al, 1996). Maintenance of cell polarity is crucial for normal di erentiation, and the localization of polarity signalling receptors to the basolateral membrane is apparently mediated by PDZ proteins (Woods and Bryant, 1993).…”

“…hDlg is expressed in a variety of cell types including epithelia, where it is localized at regions of cell-cell contact (Lue et al, 1994). Interestingly, mutations in Drosophila dlg causes epithelial cells to lose polarity and undergo neoplastic proliferation (Woods et al, 1996).…”

Scrib, un gène suppresseur de tumeurs impliqué dans la polarité cellulaire

“…De nombreuses études ont démontré le rôle de ces gènes suppresseurs de tumeur dans le contrôle du cycle cellulaire, permettant ainsi d'expliquer la prolifération exacerbée des cellules tumorales. Plus récemment, les gènes suppresseurs de tumeurs ont aussi été impliqués dans le contrôle de la polarité cellulaire [1][2][3][4][5][6][7][8][9][10][11][12]. Parmi ceux-ci, Scribble a initialement été identifié comme gène suppresseur de tumeur chez la drosophile et joue un rôle clé dans la polarité des cellules épithéliales [13].…”