Activation of Discs large by aPKC aligns the mitotic spindle to the polarity axis during asymmetric cell division

Golub, Ognjen; Wee, Brett; Newman, Rhonda A.; Paterson, Nicole M; Prehoda, Kenneth E.

doi:10.7554/elife.32137

Cited by 26 publications

(18 citation statements)

References 45 publications

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“…One of the best-characterized PDZ targets of HPV E6 is DLG1, a member of the Scrib polarity complex [4,5]. DLG1 is a scaffolding protein that coordinates the assembly of multiprotein complexes involved in the control of cell polarity, cell division, cell migration, and intracellular trafficking [6][7][8][9]. In epithelial cells, DLG1 co-localizes with E-cadherin at the adherens junctions in association with the cytoskeleton, where it has both structural and signalling functions [9,10].…”

Section: Introductionmentioning

confidence: 99%

HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

et al. 2020

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Background: Persistent infection with high-risk Human Papillomavirus (HPVs) is associated with the development of cervical cancer. The transforming capacity of these viruses relies on the cooperative action of the E6 and E7 viral oncoproteins. Among the oncogenic activities of E6, the interaction and interference with cell polarity PDZ proteins have been well established. One of the most characterized PDZ targets of HPV E6 is human Disc large 1 (DLG1), a scaffolding protein involved in the control of cell polarity and proliferation. Interestingly, in cervical squamous intraepithelial lesions, alterations in DLG1 expression were observed in association to tumour progression. Moreover, the expression of both HPV E6 and E7 proteins may be responsible for the changes in DLG1 abundance and cell localization observed in the HPV-associated lesions. Methods: Due to the relevance of DLG1 deregulation in tumour development, we have performed an in-depth investigation of the expression of DLG1 in the presence of the HPV oncoproteins in epithelial cultured cells. The effects of HPV E6 and E7 proteins on DLG1 abundance and subcellular localization were assessed by western blot and confocal fluorescence microscopy, respectively. Results: We demonstrated that the relative abundance of HPV-18 E6 and DLG1 is a key factor that contributes to defining the expression abundance of both proteins. We also show here that a high expression level of DLG1 may negatively affect HPV-18 E6 nuclear expression. Moreover, the co-expression of HPV-18 E6 and E7 produces a striking effect on DLG1 subcellular localization and a co-distribution in the cytoplasmic region. Interestingly, HPV-18 E7 is also able to increase DLG1 levels, likely by rescuing it from the E6-mediated proteasomal degradation. Conclusions: In general, the data suggest that HPV-18 E6 and E7 may have opposing activities in regards to the regulation of DLG1 levels and may cooperatively contribute to its subcellular redistribution in the HPV context. These findings constitute a step forward in understanding the differential expression of DLG1 during tumour progression in an HPV-associated model.

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Section: Introductionmentioning

confidence: 99%

HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

et al. 2020

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“…DLG1 is a component of the conserved Scribble polarity complex. Genetic and functional analyses highlighted the relevance of DLG1 in cell processes which require intracellular asymmetry, including the establishment and maintenance of cell polarity, as well as asymmetric cell division and cell migration (Knoblich, 2008;O'Neill et al, 2011;Golub et al, 2017;Stephens et al, 2018). In epithelial cells, DLG1 is localized to the adherens junctions in association with components of the cytoskeleton, where it coordinates junction formation and stability while contributing to the maintenance of apical-basal polarity (Laprise et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology

Marziali

Dizanzo

Cavatorta

et al. 2019

Biological Chemistry

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Human disc large (DLG1) is a scaffolding protein that through the interaction with diverse cell partners participates in the control of key cellular processes such as polarity, proliferation and migration. Experimental data have mainly identified DLG1 as a tumor suppressor. An outstanding point for DLG1 protein is that altered DLG1 expression andDLG1gene mutations were observed in different pathologies, including cancer and neurological and immunological disorders. Evident changes in DLG1 abundance and/or cell localization were identified in a number of studies suggesting its participation in molecular mechanisms responsible for the development of such illnesses. In this review, we focus on some of the latest findings regarding DLG1 alterations in different diseases as well as its potential use as a biomarker for pathological progression. We further address the current knowledge on the molecular mechanisms regulating DLG1 expression and the posttranslational modifications that may affect DLG1 cell localization and functions. Despite the advances in this field, there are still open questions about the precise molecular link between alterations in DLG1 expression and the development of each specific pathology. The complete understanding of this concern will give us new scenarios for the design of promising diagnosis and therapeutic tools.

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“…Further work is required to characterize how Dlg and Scrib suppress apical determination. Since Dlg is itself an aPKC substrate(Golub et al, 2017), Dlg could buffer aPKC activity towards other substrates. This could promote Lgl accumulation at the cortex, and concomitantly prevent aPKC lateral extension by inhibiting the aPKC-mediated stabilization of apical complexes in the lateral cortex…”

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confidence: 99%

Lgl cortical dynamics are independent of binding to the Scrib-Dlg complex but require Dlg-dependent restriction of aPKC

Ventura

Moreira

Barros-Carvalho

et al. 2019

Preprint

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Apical-basal polarity underpins the formation of specialized epithelial barriers that are critical for metazoan physiology. Although apical-basal polarity is long known to require the basolateral determinants Lethal Giant Larvae (Lgl), Discs Large (Dlg) and Scribble (Scrib), mechanistic understanding of their function is limited. Lgl plays a role as an aPKC inhibitor, but it remains unclear whether Lgl also forms a complex with Dlg or Scrib. Using fluorescence recovery after photobleaching, we show that Lgl does not form immobile complexes at the lateral domain of Drosophila follicle cells. Optogenetic depletion of plasma membrane phosphatidylinositol 4,5-biphosphate (PIP2) or Dlg removal accelerate Lgl cortical dynamics. However, whereas Lgl turnover relies on PIP2 binding, Dlg and Scrib are only required for Lgl localization and dynamic behavior in the presence of aPKC function. Furthermore, lightinduced oligomerization of basolateral proteins indicate that Lgl is not part of the Scrib-Dlg complex in vivo. Thus, Scrib-Dlg are necessary to repress aPKC activity in the lateral domain but do not provide cortical binding sites for Lgl. Our work therefore highlights that Lgl does not act in a complex but in parallel with Scrib-Dlg to antagonize apical determinants.

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Activation of Discs large by aPKC aligns the mitotic spindle to the polarity axis during asymmetric cell division

Cited by 26 publications

References 45 publications

HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology

Lgl cortical dynamics are independent of binding to the Scrib-Dlg complex but require Dlg-dependent restriction of aPKC

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