Girdin is a component of the lateral polarity protein network restricting cell dissemination

Mapping Intimacies ◽

10.1101/733329 ◽

2019 ◽

Author(s):

Cornélia Biehler ◽

Li-Ting Wang ◽

Myriam Sévigny ◽

Alexandra Jetté ◽

Clémence Gamblin ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Polarity ◽

Cancer Progression ◽

Cell Polarization ◽

Protein Network ◽

Poor Overall Survival ◽

Lung Cancers ◽

Epithelial Cancers ◽

Human Ortholog ◽

Cell Dissemination

AbstractEpithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with a poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.

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A bidirectional antagonism between aPKC and Yurt regulates epithelial cell polarity

The Journal of Cell Biology ◽

10.1083/jcb.201308032 ◽

2014 ◽

Vol 204 (4) ◽

pp. 487-495 ◽

Cited By ~ 27

Author(s):

Clémence L. Gamblin ◽

Émilie J.-L. Hardy ◽

François J.-M. Chartier ◽

Nicolas Bisson ◽

Patrick Laprise

Keyword(s):

Epithelial Cell ◽

Cell Polarity ◽

Cell Polarization ◽

Membrane Domains ◽

Epithelial Cell Polarity ◽

Kinase C ◽

The Stability ◽

Regulatory Loop ◽

Late Stages ◽

Apical Localization

During epithelial cell polarization, Yurt (Yrt) is initially confined to the lateral membrane and supports the stability of this membrane domain by repressing the Crumbs-containing apical machinery. At late stages of embryogenesis, the apical recruitment of Yrt restricts the size of the apical membrane. However, the molecular basis sustaining the spatiotemporal dynamics of Yrt remains undefined. In this paper, we report that atypical protein kinase C (aPKC) phosphorylates Yrt to prevent its premature apical localization. A nonphosphorylatable version of Yrt dominantly dismantles the apical domain, showing that its aPKC-mediated exclusion is crucial for epithelial cell polarity. In return, Yrt counteracts aPKC functions to prevent apicalization of the plasma membrane. The ability of Yrt to bind and restrain aPKC signaling is central for its role in polarity, as removal of the aPKC binding site neutralizes Yrt activity. Thus, Yrt and aPKC are involved in a reciprocal antagonistic regulatory loop that contributes to segregation of distinct and mutually exclusive membrane domains in epithelial cells.

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The PTEN Phosphatase Controls Intestinal Epithelial Cell Polarity and Barrier Function: Role in Colorectal Cancer Progression

PLoS ONE ◽

10.1371/journal.pone.0015742 ◽

2010 ◽

Vol 5 (12) ◽

pp. e15742 ◽

Cited By ~ 52

Author(s):

Marie-Josée Langlois ◽

Sébastien Bergeron ◽

Gérald Bernatchez ◽

François Boudreau ◽

Caroline Saucier ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Cell ◽

Cell Polarity ◽

Cancer Progression ◽

Barrier Function ◽

Intestinal Epithelial Cell ◽

Intestinal Epithelial ◽

Epithelial Cell Polarity ◽

Colorectal Cancer Progression

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Crumbs interacts with moesin and βHeavy-spectrin in the apical membrane skeleton of Drosophila

The Journal of Cell Biology ◽

10.1083/jcb.200203080 ◽

2002 ◽

Vol 158 (5) ◽

pp. 941-951 ◽

Cited By ~ 119

Author(s):

Emmanuelle Médina ◽

Janice Williams ◽

Elizabeth Klipfell ◽

Daniela Zarnescu ◽

Graham Thomas ◽

...

Keyword(s):

Cell Polarity ◽

Apical Membrane ◽

Transmembrane Protein ◽

Membrane Skeleton ◽

Cell Polarization ◽

Epithelial Morphogenesis ◽

Protein Network ◽

Ferm Domain ◽

Junctional Region ◽

Domain Protein

The apical transmembrane protein Crumbs is necessary for both cell polarization and the assembly of the zonula adherens (ZA) in Drosophila epithelia. The apical spectrin-based membrane skeleton (SBMS) is a protein network that is essential for epithelial morphogenesis and ZA integrity, and exhibits close colocalization with Crumbs and the ZA in fly epithelia. These observations suggest that Crumbs may stabilize the ZA by recruiting the SBMS to the junctional region. Consistent with this hypothesis, we report that Crumbs is necessary for the organization of the apical SBMS in embryos and Schneider 2 cells, whereas the localization of Crumbs is not affected in karst mutants that eliminate the apical SBMS. Our data indicate that it is specifically the 4.1 protein/ezrin/radixin/moesin (FERM) domain binding consensus, and in particular, an arginine at position 7 in the cytoplasmic tail of Crumbs that is essential to efficiently recruit both the apical SBMS and the FERM domain protein, DMoesin. Crumbs, Discs lost, βHeavy-spectrin, and DMoesin are all coimmunoprecipitated from embryos, confirming the existence of a multimolecular complex. We propose that Crumbs stabilizes the apical SBMS via DMoesin and actin, leading to reinforcement of the ZA and effectively coupling epithelial morphogenesis and cell polarity.

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Epithelial Cell Transforming 2 (ECT2) is regulated by Yes-associated protein 1 (YAP1) and mediates pancreatic cancer progression and metastasis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00185.2020 ◽

2021 ◽

Author(s):

Ce Li ◽

Zhenzi Peng ◽

Yizhou Wang ◽

Gloria Lam ◽

Nicholas Nissen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Epithelial Cell ◽

Mouse Model ◽

Cancer Progression ◽

Critical Role ◽

Ductal Adenocarcinoma ◽

Cancer Growth ◽

Nucleotide Exchange ◽

Poor Overall Survival ◽

Cell Transforming

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of Kras and Trp53. Notably, nuclear ECT2 is upregulated in the transition from pre-neoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with poor overall survival rate of PDAC patients. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight a critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into development of novel methods for early detection and treatment.

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Cell polarity in morphogenesis and metastasis

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2013.0012 ◽

2013 ◽

Vol 368 (1629) ◽

pp. 20130012 ◽

Cited By ~ 33

Author(s):

Ian G. Macara ◽

Luke McCaffrey

Keyword(s):

Epithelial Cells ◽

Cell Polarity ◽

Cancer Cell ◽

Cancer Progression ◽

Tumour Growth ◽

Conclusive Evidence ◽

Mesenchymal Transition ◽

Metastatic Colonization ◽

Metastatic Growth ◽

Cell Dissemination

Most human cancers arise either from epithelial cells or their progenitors. Epithelial cells possess a distinctive apical–basal polarity and loss of polarity is frequently assumed to be a common feature of cancer progression. In particular, cancer cell dissemination to ectopic sites, and metastatic growth at those sites, is often considered to require a mesenchymal transition in which the transformed epithelial cells lose their apical–basal polarity. However, many cancers retain epithelial characteristics, and until recently there has been little conclusive evidence for an involvement of the cell polarity machinery in tumour growth and metastasis. In this article, we discuss evidence that polarity proteins can be potent invasion suppressors but that loss of epithelial character is not essential either for tumour growth and invasion, or metastatic colonization.

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Lethal giant larvae proteins interact with the exocyst complex and are involved in polarized exocytosis

The Journal of Cell Biology ◽

10.1083/jcb.200502055 ◽

2005 ◽

Vol 170 (2) ◽

pp. 273-283 ◽

Cited By ~ 72

Author(s):

Xiaoyu Zhang ◽

Puyue Wang ◽

Akanksha Gangar ◽

Jian Zhang ◽

Patrick Brennwald ◽

...

Keyword(s):

Plasma Membrane ◽

Epithelial Cell ◽

Membrane Fusion ◽

Cell Polarity ◽

Rho Gtpases ◽

Critical Role ◽

Cell Polarization ◽

Snare Proteins ◽

Exocyst Complex ◽

Lethal Giant Larvae

The tumor suppressor lethal giant larvae (Lgl) plays a critical role in epithelial cell polarization. However, the molecular mechanism by which Lgl carries out its functions is unclear. In this study, we report that the yeast Lgl proteins Sro7p and Sro77p directly interact with Exo84p, which is a component of the exocyst complex that is essential for targeting vesicles to specific sites of the plasma membrane for exocytosis, and that this interaction is important for post-Golgi secretion. Genetic analyses demonstrate a molecular pathway from Rab and Rho GTPases through the exocyst and Lgl to SNAREs, which mediate membrane fusion. We also found that overexpression of Lgl and t-SNARE proteins not only improves exocytosis but also rescues polarity defects in exocyst mutants. We propose that, although Lgl is broadly distributed in the cells, its localized interaction with the exocyst and kinetic activation are important for the establishment and reenforcement of cell polarity.

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The Transforming Rho Family GTPase Wrch-1 Disrupts Epithelial Cell Tight Junctions and Epithelial Morphogenesis

Molecular and Cellular Biology ◽

10.1128/mcb.00336-08 ◽

2008 ◽

Vol 29 (4) ◽

pp. 1035-1049 ◽

Cited By ~ 36

Author(s):

Donita C. Brady ◽

Jamie K. Alan ◽

James P. Madigan ◽

Alan S. Fanning ◽

Adrienne D. Cox

Keyword(s):

Epithelial Cell ◽

Cell Polarity ◽

Rho Gtpase ◽

Mdck Cells ◽

3D Culture ◽

Cell Polarization ◽

Epithelial Morphogenesis ◽

Detectable Effect ◽

Dependent Manner ◽

Actin Organization

ABSTRACT Wrch-1, an atypical and transforming Rho GTPase, regulates cellular activities including proliferation and actin organization, but its functions and effectors remain poorly characterized. We show here that Wrch-1 distributes along the apical and basolateral membranes in MDCK cells and binds the cell polarity protein Par6 in a GTP-dependent manner. Activated Wrch-1 negatively regulates the kinetics of tight junction (TJ) assembly during epithelial cell polarization but has no detectable effect on overall cell polarity in confluent monolayers. It also causes a dramatic cytoskeletal reorganization and multilayering in cells grown in two-dimensional culture and disrupts cystogenesis of cells grown in three-dimensional (3D) culture. Similarly, short hairpin RNA-mediated knockdown of Wrch-1 perturbs cystogenesis in 3D culture, suggesting that tight regulation of Wrch-1 activity is necessary for normal epithelial morphogenesis. A weakly transforming effector domain mutant of activated Wrch-1 that inhibits Par6 binding abrogates the ability of Wrch-1 to disrupt TJ formation, actin organization, and epithelial morphogenesis. We hypothesize that Wrch-1-induced morphological and growth transformation may occur in part through Par6-mediated disruption of TJs and actin organization.

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Apicobasal polarity and its role in cancer progression

BioMolecular Concepts ◽

10.1515/bmc-2012-0020 ◽

2012 ◽

Vol 3 (6) ◽

pp. 505-521 ◽

Cited By ~ 4

Author(s):

Priscilla Lo ◽

Hannah Hawrot ◽

Marios Georgiou

Keyword(s):

Epithelial Cell ◽

Cell Polarity ◽

Cancer Progression ◽

Cell Invasion ◽

Normal Development ◽

Tumour Progression ◽

Invasion And Metastasis ◽

Human Cancers ◽

Apicobasal Polarity ◽

Tumour Cell Invasion

AbstractAppropriate establishment and maintenance of cell polarity is essential for normal development and homeostasis. The vast majority of human cancers originate from epithelial tissues and tumour cell invasion and metastasis are the major cause of mortality in human cancers. Invading cells demonstrate loss of cell polarity, loss of epithelial cell-cell adhesions and tissue disorganisation. We examine the growing evidence linking loss of apicobasal polarity with tumour progression.

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