The Scribble–Dlg–Lgl polarity module in development and cancer: from flies to man

2012 ◽  
Vol 53 ◽  
pp. 141-168 ◽  
Author(s):  
Imogen Elsum ◽  
Laura Yates ◽  
Patrick O. Humbert ◽  
Helena E. Richardson
Keyword(s):  
Cell Polarity ◽  
Cancer Progression ◽  
Basal Cell ◽  
Cell Signalling ◽  
Fruit Fly ◽  
Strongly Correlated ◽  
Tissue Architecture ◽  
Discs Large ◽  
Lethal Giant Larvae

The Scribble, Par and Crumbs modules were originally identified in the vinegar (fruit) fly, Drosophila melanogaster, as being critical regulators of apico–basal cell polarity. In the present chapter we focus on the Scribble polarity module, composed of Scribble, discs large and lethal giant larvae. Since the discovery of the role of the Scribble polarity module in apico–basal cell polarity, these proteins have also been recognized as having important roles in other forms of polarity, as well as regulation of the actin cytoskeleton, cell signalling and vesicular trafficking. In addition to these physiological roles, an important role for polarity proteins in cancer progression has also been uncovered, with loss of polarity and tissue architecture being strongly correlated with metastatic disease.

scholarly journals Electrostatic plasma membrane targeting contributes to Dlg function in cell polarity and tumorigenesis

Development ◽  
2021 ◽  
pp. dev.196956
Author(s):  
Juan Lu ◽  
Wei Dong ◽  
Yan Tao ◽  
Yang Hong
Keyword(s):  
Plasma Membrane ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cell Polarity ◽  
Significant Role ◽  
Discs Large ◽  
Cortical Localization ◽  
Polarity Proteins ◽  
Positively Charged

Discs large (Dlg) is an essential polarity protein and a tumor suppressor originally characterized in Drosophila but is also well conserved in vertebrates. Like the majority of polarity proteins, plasma membrane (PM)/cortical localization of Dlg is required for its function in polarity and tumorigenesis, but the exact mechanisms targeting Dlg to PM remain to be fully elucidated. Here we show that, similar to the recently discovered polybasic polarity proteins such as Lgl and aPKC, Dlg also contains a positively charged polybasic domain that electrostatically binds the PM phosphoinositides PI4P and PI(4,5)P2. Electrostatic targeting by the polybasic domain contributes significantly to the PM localization of Dlg in follicular and early embryonic epithelial cells, and is crucial for Dlg to regulate both polarity and tumorigenesis. The electrostatic PM targeting of Dlg is controlled by a potential phosphorylation-dependent allosteric regulation of its polybasic domain, and is specifically enhanced by the interactions between Dlg and another basolateral polarity protein and tumor suppressor Scrib. Our studies highlight an increasingly significant role of electrostatic PM targeting of polarity proteins in regulating cell polarity.

scholarly journals Drosophila aPKC regulates cell polarity and cell proliferation in neuroblasts and epithelia

2003 ◽  
Vol 163 (5) ◽  
pp. 1089-1098 ◽  
Author(s):  
Melissa M. Rolls ◽  
Roger Albertson ◽  
Hsin-Pei Shih ◽  
Cheng-Yu Lee ◽  
Chris Q. Doe
Keyword(s):  
Cell Proliferation ◽  
Cell Polarity ◽  
Cell Types ◽  
Proper Function ◽  
Larval Stages ◽  
Kinase C ◽  
Discs Large ◽  
Lethal Giant Larvae ◽  
Cell Diversity ◽  
Apical Localization

Cell polarity is essential for generating cell diversity and for the proper function of most differentiated cell types. In many organisms, cell polarity is regulated by the atypical protein kinase C (aPKC), Bazooka (Baz/Par3), and Par6 proteins. Here, we show that Drosophila aPKC zygotic null mutants survive to mid-larval stages, where they exhibit defects in neuroblast and epithelial cell polarity. Mutant neuroblasts lack apical localization of Par6 and Lgl, and fail to exclude Miranda from the apical cortex; yet, they show normal apical crescents of Baz/Par3, Pins, Inscuteable, and Discs large and normal spindle orientation. Mutant imaginal disc epithelia have defects in apical/basal cell polarity and tissue morphology. In addition, we show that aPKC mutants show reduced cell proliferation in both neuroblasts and epithelia, the opposite of the lethal giant larvae (lgl) tumor suppressor phenotype, and that reduced aPKC levels strongly suppress most lgl cell polarity and overproliferation phenotypes.

scholarly journals The Case of the Scribble Polarity Module in Asymmetric Neuroblast Division in Development and Tumorigenesis

2020 ◽  
Vol 21 (8) ◽  
pp. 2865
Author(s):  
Ana Carmena
Keyword(s):  
Epithelial Cell ◽  
Tumor Suppressor ◽  
Cell Polarity ◽  
Tumor Suppressor Genes ◽  
Asymmetric Division ◽  
Suppressor Genes ◽  
Epithelial Cell Polarity ◽  
Discs Large ◽  
Underlying Mechanisms

The Scribble polarity module is composed by Scribble (Scrib), Discs large 1 (Dlg1) and Lethal (2) giant larvae (L(2)gl), a group of highly conserved neoplastic tumor suppressor genes (TSGs) from flies to humans. Even though the Scribble module has been profusely studied in epithelial cell polarity, the number of tissues and processes in which it is involved is increasingly growing. Here we discuss the role of the Scribble module in the asymmetric division of Drosophila neuroblasts (NBs), as well as the underlying mechanisms by which those TSGs act in this process. Finally, we also describe what we know about the consequences of mutating these genes in impairing the process of asymmetric NB division and promoting tumor-like overgrowth.

scholarly journals Cancer-associated fibroblasts suppress SOX2-induced dysplasia in a lung squamous cancer coculture

2018 ◽  
Vol 115 (50) ◽  
pp. E11671-E11680 ◽  
Author(s):  
Shuang Chen ◽  
Andreas Giannakou ◽  
Sarah Wyman ◽  
Janet Gruzas ◽  
Jonathon Golas ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Polarity ◽  
Squamous Carcinoma ◽  
Phenotypic Switching ◽  
Cancer Associated Fibroblasts ◽  
Disease Phenotype ◽  
Tissue Architecture ◽  
Squamous Cancer ◽  
Lung Squamous Carcinoma

Tumorigenesis depends on intricate interactions between genetically altered tumor cells and their surrounding microenvironment. While oncogenic drivers in lung squamous carcinoma (LUSC) have been described, the role of stroma in modulating tissue architecture, particularly cell polarity, remains unclear. Here, we report the establishment of a 3D coculture system of LUSC epithelial cells with cancer-associated fibroblasts (CAFs) and extracellular matrix that together capture key components of the tumor microenvironment (TME). Single LUSC epithelial cells develop into acinar-like structures with 0.02% efficiency, and addition of CAFs provides proper tumor−stromal interactions within an appropriate 3D architectural context. Using this model, we recapitulate key pathological changes during tumorigenesis, from hyperplasia to dysplasia and eventually invasion, in malignant LUSC spheroids that undergo phenotypic switching in response to cell intrinsic and extrinsic changes. Overexpression of SOX2 is sufficient to mediate the transition from hyperplasia to dysplasia in LUSC spheroids, while the presence of CAFs makes them invasive. Unexpectedly, CAFs suppress the activity of high SOX2 levels, restore hyperplasia, and enhance the formation of acinar-like structures. Taken together, these observations suggest that stromal factors can override cell intrinsic oncogenic changes in determining the disease phenotype, thus providing fundamental evidence for the existence of dynamic reciprocity between the nucleus and the TME of LUSC.

scholarly journals Electrostatic Plasma Membrane Targeting is Essential for Dlg Function in Cell Polarity and Tumorigenesis

2020 ◽  
Author(s):  
Juan Lu ◽  
Wei Dong ◽  
Yan Tao ◽  
Yang Hong
Keyword(s):  
Plasma Membrane ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cell Polarity ◽  
Primary Mechanism ◽  
Discs Large ◽  
Cortical Localization ◽  
Polarity Proteins ◽  
Positively Charged

SUMMARYDiscs large (Dlg) is an essential polarity protein and a tumor suppressor originally characterized in Drosophila but is also well conserved in vertebrates. Like the majority of polarity proteins, plasma membrane (PM)/cortical localization of Dlg is required for its function in regulating apical-basal polarity and tumorigenesis, but the exact mechanisms targeting Dlg to PM remain to be unclear. Here we show that, similar to recently discovered polybasic polarity proteins such as Lgl and aPKC, Dlg also contains a positively charged polybasic domain that electrostatically binds the PM phosphoinositides PI4P and PI(4,5)P2. Electrostatic targeting by the polybasic domain acts as the primary mechanism localizing Dlg to the PM in follicular and early embryonic epithelial cells, and is crucial for Dlg to regulate both polarity and tumorigenesis. The electrostatic PM targeting of Dlg is controlled by a potential phosphorylation-dependent allosteric regulation of its polybasic domain, and is specifically enhanced by interactions between Dlg and another basolateral polarity protein and tumor suppressor Scrib. Our studies highlight an increasingly significant role of electrostatic PM targeting of polarity proteins in regulating cell polarity.

scholarly journals Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States

2021 ◽  
Vol 10 (11) ◽  
pp. 2403
Author(s):  
Laura Bornes ◽  
Guillaume Belthier ◽  
Jacco van Rheenen
Keyword(s):  
Wound Healing ◽  
Cell Adhesion ◽  
Basement Membrane ◽  
Cell Polarity ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Therapy Resistance ◽  
Mesenchymal Transition

Epithelial-to-mesenchymal transition (EMT) is a cellular program which leads to cells losing epithelial features, including cell polarity, cell–cell adhesion and attachment to the basement membrane, while gaining mesenchymal characteristics, such as invasive properties and stemness. This program is involved in embryogenesis, wound healing and cancer progression. Over the years, the role of EMT in cancer progression has been heavily debated, and the requirement of this process in metastasis even has been disputed. In this review, we discuss previous discrepancies in the light of recent findings on EMT, plasticity and hybrid E/M states. Moreover, we highlight various tumor microenvironmental cues and cell intrinsic signaling pathways that induce and sustain EMT programs, plasticity and hybrid E/M states. Lastly, we discuss how recent findings on plasticity, especially on those that enable cells to switch between hybrid E/M states, have changed our understanding on the role of EMT in cancer metastasis, stemness and therapy resistance.

scholarly journals Deregulation of the cell polarity protein Lethal giant larvae 2 (Lgl2) correlates with gastric cancer progression

2013 ◽  
Vol 17 (4) ◽  
pp. 610-620 ◽  
Author(s):  
Kyung Han Nam ◽  
Min A. Kim ◽  
Gheeyoung Choe ◽  
Woo Ho Kim ◽  
Hye Seung Lee
Keyword(s):  
Gastric Cancer ◽  
Cell Polarity ◽  
Cancer Progression ◽  
Lethal Giant Larvae ◽  
Gastric Cancer Progression

scholarly journals The role of neurological involvement in malignant tissues: architecture deterioration as a new medical hypothesis explaining cancer progression

2021 ◽  
Vol 11 (3) ◽  
pp. 70-71
Author(s):  
Ahed J Alkhatib
Keyword(s):  
Cancer Progression ◽  
Relevant Literature ◽  
Neurological Involvement ◽  
Diabetic Rat ◽  
Tissue Architecture ◽  
Medical Hypothesis ◽  
Oxide Synthase ◽  
Kidney Liver ◽  
Inducible Nitric Oxide

In this study, we reported our previous observations and perceptions regarding the involvement of neurological components in the malignant tissues. We used to examine different tissues with malignancy, and we observed increased involvement of neurological components as peripheral nerves. At the beginning, no plausible explanation to such phenomenon. Later, we showed in diabetic rat model that white matter was involved in diabetic progression through the up-regulation of inducible nitric oxide synthase (iNOS) and the down-regulation of heat shock protein70 (HSP70). We extended our investigations in other organs in the same model including kidney, liver, testes, and prostate. We found the same phenomenon of the expression of iNOS and HSP70 in the tissues of these organs. We also observed that there was a deterioration of tissue architecture due to diabetic effects. We think that this deterioration may result from the neurological involvement in these tissues. However, because diabetes may result in initiation of some tumors such as endometrium cancer, deterioration of tissue architecture and neurological involvement are becoming more importantly. This study aimed to introduce our hypothesis in this issue “Architecture deterioration as a new medical hypothesis explaining cancer progression”. We also reviewed the relevant literature.

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