Polarity proteins in migration and invasion

Etienne-Manneville, Sandrine

doi:10.1038/onc.2008.347

Cited by 262 publications

(239 citation statements)

References 119 publications

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“…In this study, we showed that Scrib, a pivotal cell polarity module 21 with putative tumor suppression functions, 1,3 is almost universally overexpressed and subcellularly mislocalized in disparate human cancers, in vivo, independently of oncogenic signaling or viral (ie, HPV) transformation. Nevertheless, Scrib diffusion into the cytoplasm could also be related to saturation of membrane-free positions consequent to Scrib overexpression.…”

Section: Discussionmentioning

confidence: 87%

“…21 This further contributes to the acquisition of a migratory epithelial-mesenchymal transition-like cellular phenotype. In this context, therapeutic targeting of the Scrib pathway may selectively disrupt pivotal mechanisms of random tumor cell motility and invasion 22 in tumors, creating concrete new prospects for the development of directed antimetastatic therapies in humans.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

Vaira¹,

Faversani²,

Dohi³

et al. 2011

The American Journal of Pathology

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Human Scribble (Scrib) is an evolutionary-conserved cell polarity protein, but its potential role in human cancer is controversial. Herein, we show that Scrib is nearly universally overexpressed in cultured tumor cell lines and genetically disparate cancer patient series compared with matched normal tissues in vivo. Instead of a membrane association seen in normal epithelia, tumor-associated Scrib is mislocalized and found predominantly in the cytosol. Small-interfering RNA silencing of Scrib in model lung adenocarcinoma A549 cells inhibited cell migration in wound-healing assays, suppressed tumor cell invasion across Matrigelcoated inserts, and down-regulated the expression of cell motility markers and mediators of epithelial-mesenchymal transition. These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

Vaira¹,

Faversani²,

Dohi³

et al. 2011

The American Journal of Pathology

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“…One of the earliest steps in EMT is the loss of cell-cell adhesion and disruption of apical-basal cell polarity, as well as increased motility of cells. In migrating cells, polarity proteins are important regulators of front-back polarity; many cell polarity proteins (including Scribble, Par3 and Par6) are localized to the leading edge of migrating cells and play important roles during directional migration 32 . Migration of cells is associated with changes in cell architecture, suggesting that cell polarity proteins play important roles during this process.…”

Section: Discussionmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…Note also that 3 and 5 pg of DN-Cdc42 mRNA alone dramatically impacted the morphology and decreased the survival of the embryos to 20-to 24-somite stages. These results suggest not only that Cdc42 is an essential downstream effecter of p120 catenin d1 for normal cell migration, but also that the ability of Cdc42 to initiate directional polarity of migrating cells by localized GDP to GTP exchange (Etteinne-Manneville, 2004, 2008Etteinne-Manneville and Hall 2001;Yang et al, 2006;Johnson et al, 2010) or to cycle between its active GTP-bound and inactive GDPbound states is an essential feature in this signaling pathway.…”

Section: Defects From Knockdown Of P120 Catenin D1 Persist In Later-smentioning

confidence: 90%

“…To investigate our hypothesis that the polarized regulation of Rho GTPases by p120 catenin d1 is necessary during gastrulation, we examined the ability of various forms of Cdc42 to rescue the d1 splice-MO phenotype. Cdc42 is a small (191 amino acids) member of the Rho GTPases that is crucial for the formation of filopodia along the leading edge of migrating vertebrate cells (Etienne-Manneville and Hall, 2001;Choi and Han, 2003;Etienne-Manneville, 2004, 2008Yang Developmental Dynamics Fig. 5.…”

Section: Defects From Knockdown Of P120 Catenin D1 Persist In Later-smentioning

confidence: 99%

Cdc42 GTPase and Rac1 GTPase act downstream of p120 catenin and require GTP exchange during gastrulation of zebrafish mesoderm

Hsu

Muerdter

Knickerbocker

et al. 2012

Developmental Dynamics

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Background: We investigated the roles of p120 catenin, Cdc42, Rac1, and RhoA GTPases in regulating migration of presomitic mesoderm cells in zebrafish embryos. p120 catenin has dual roles: It binds the intracellular and juxtamembrane region of cadherins to stabilize cadherin-mediated adhesion with the aid of RhoA GTPase, and it activates Cdc42 GTPase and Rac1 GTPase in the cytosol to initiate cell motility. Results: During gastrulation of zebrafish embryos, knockdown of the synthesis of zygotic p120 catenind1 mRNAs with a splice-site morpholino caused lateral widening and anterior-posterior shortening of the presomitic mesoderm and somites and a shortened anterior-posterior axis. These phenotypes indicate a cell-migration effect. Co-injection of low amounts of wild-type Cdc42 or wild-type Rac1 or dominant-negative RhoA mRNAs, but not constitutively-active Cdc42 mRNA, rescued these p120 catenin d1-depleted embryos. Conclusions: These downstream small GTPases require appropriate spatiotemporal stimulation or cycling of GTP to guide mesodermal cell migration. A delicate balance of Rho GTPases and p120 catenin underlies normal development. Developmental Dynamics 241:1545-1561, 2012. V C 2012 Wiley Periodicals Inc.Key words: p120 Catenin (CTNND1); ARVCF; Delta-catenin (CTNND2b); Cdc42 GTPase; Rac1 GTPase, RhoA GTPase; gastrulation; presomitic mesoderm; somites; zebrafish Key findings p120 catetin is required for extension of the dorsal axis and normal migration of the presomitic mesoderm. Cdc42 and Rac1 GTPases are downstream of p120 catenin d1 signaling and require exchange of GTP for GDP. Local stimulation of the exchange of GTP for GDP in Cdc42 and Rac GTPases mediates directional migration of the presomitic mesoderm. A balance of the amount of p120 catenin d1 and localized activation or turnover of Cdc42, Rac1, and Rho GTPase are required for normal zebrafish cell migration. Accepted 31 July 2012 Developmental DynamicsABBREVIATIONS Ab antibody ARVCF armadillo repeat gene deleted in velo-cardio-facial syndrome CA constitutively active Chr chromosome C(t) relative amount of RT-PCR product hpf hours post-fertilization DN dominant negative d1 splice-MO antisense morpholino oligonucleotide to the 12 th splice site of zebrafish p120 catenin d1 p120 catenin d1 (CTNND1) also called p120 catenin, Xenopus p120 catenin is a CTNND1 p120 catenin d2b (CTNND2b) also called Delta-catenin Rok1 Rho kinase1 RT reverse transcriptase minus-RT controls without reverse transcriptase qRT-PCR quantitative real-time PCR WT wild-type Xp120 catenin mRNA Xenopus p120 catenin d1 mRNA.Additional Supporting Information may be found in the online version of this article.

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Polarity proteins in migration and invasion

Cited by 262 publications

References 119 publications

Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Cdc42 GTPase and Rac1 GTPase act downstream of p120 catenin and require GTP exchange during gastrulation of zebrafish mesoderm

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