The N-cadherin cytoplasmic domain confers anchorage-independent growth and the loss of contact inhibition

Ozawa, Masayuki

doi:10.1038/srep15368

Cited by 14 publications

(11 citation statements)

References 60 publications

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“…Cadherin-11 promotes lamellipodia and filopodia formation and cell migration via activation of the Trio GEF 125 . N-cadherin promotes anchorage-independent growth via loss of contact inhibition 126 and protects from bile acid-induced apoptosis in hepatocellular carcinomas 127 . N-cadherin also facilitates FGF receptor and PDGF receptor activities, thus promoting cell motility and metastatic behavior 128,129 .…”

Section: Cadherins and Emtmentioning

confidence: 99%

A central role for cadherin signaling in cancer

Kourtidis

Pence

et al. 2017

Experimental Cell Research

224

220

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Cadherins are homophilic adhesion molecules with important functions in cell-cell adhesion, tissue morphogenesis, and cancer. In epithelial cells, E-cadherin accumulates at areas of cell-cell contact, coalesces into macromolecular complexes to form the adherens junctions (AJs), and associates via accessory partners with a subcortical ring of actin to form the apical zonula adherens (ZA). As a master regulator of the epithelial phenotype, E-cadherin is essential for the overall maintenance and homeostasis of polarized epithelial monolayers. Its expression is regulated by a host of genetic and epigenetic mechanisms related to cancer, and its function is modulated by mechanical forces at the junctions, by direct binding and phosphorylation of accessory proteins collectively termed catenins, by endocytosis, recycling and degradation, as well as, by multiple signaling pathways and developmental processes, like the epithelial to mesenchymal transition (EMT). Nuclear signaling mediated by the cadherin associated proteins β-catenin and p120 promotes growth, migration and pluripotency. Receptor tyrosine kinase, PI3K/AKT, Rho GTPase, and HIPPO signaling, are all regulated by E-cadherin mediated cell-cell adhesion. Finally, the recruitment of the microprocessor complex to the ZA by PLEKHA7, and the subsequent regulation of a small subset of miRNAs provide an additional mechanism by which the state of epithelial cell-cell adhesion affects translation of target genes to maintain the homeostasis of polarized epithelial monolayers. Collectively, the data indicate that loss of E-cadherin function, especially at the ZA, is a common and crucial step in cancer progression.

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Section: Cadherins and Emtmentioning

confidence: 99%

A central role for cadherin signaling in cancer

Kourtidis

Pence

et al. 2017

Experimental Cell Research

224

220

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“…SPCA2 is an upstream regulator of YAP and Hippo pathway signaling E-cadherin is required for cell-adhesion and contact inhibition of proliferation (34). By activating the Hippo tumor-suppressor signaling pathway, E-cadherin controls phosphorylation, inactivation, and nuclear exclusion of YAP, resulting in inhibition of cell proliferation in normal human mammary epithelial and breast cancer cells (Fig.…”

Section: Spca2 Phenocopies E-cadherin In Tumorsphere Formationmentioning

confidence: 99%

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells

Dang

Makena

Llongueras

et al. 2019

Molecular Cancer Research

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Progression of benign tumors to invasive, metastatic cancer is accompanied by the epithelial-to-mesenchymal transition (EMT), characterized by loss of the cell-adhesion protein E-cadherin. Although silencing mutations and transcriptional repression of the E-cadherin gene have been widely studied, not much is known about posttranslational regulation of E-cadherin in tumors. We show that E-cadherin is tightly coexpressed with the secretory pathway Ca 2þ -ATPase isoform 2, SPCA2 (ATP2C2), in breast tumors. Loss of SPCA2 impairs surface expression of E-cadherin and elicits mesenchymal gene expression through disruption of cell adhesion in tumorspheres and downstream Hippo-YAP signaling. Conversely, ectopic expression of SPCA2 in triple-negative breast cancer elevates baseline Ca 2þ and YAP phosphorylation, enhances posttranslational expression of E-cadherin, and suppresses mesenchymal gene expression. Thus, loss of SPCA2 phenocopies loss of E-cadherin in the Hippo signaling pathway and EMT-MET transitions, consistent with a functional role for SPCA2 in E-cadherin biogenesis. Furthermore, we show that SPCA2 suppresses invasive phenotypes, including cell migration in vitro and tumor metastasis in vivo. Based on these findings, we propose that SPCA2 functions as a key regulator of EMT and may be a potential therapeutic target for treatment of metastatic cancer.Implications: Posttranslational control of E-cadherin and the Hippo pathway by calcium signaling regulates EMT in breast cancer cells.

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“…E-cadherin is required for cell-adhesion and contact inhibition of proliferation (34). By activating the Hippo tumor suppressor signaling pathway, E-cadherin controls phosphorylation, inactivation and nuclear exclusion of YAP, resulting in inhibition of cell proliferation in normal human mammary epithelial and breast cancer cells ( Fig.…”

Section: Spca2 Is An Upstream Regulator Of Yap and Hippo Pathway Signmentioning

confidence: 99%

A Ca²⁺-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

Dang

Makena

Llongueras

et al. 2018

Preprint

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SummaryProgression of benign tumors to invasive, metastatic cancer requires loss of the celladhesion protein E-cadherin. Although intensive efforts have focused on gene repression and silencing mutations, much less is known about posttranslational control of E-cadherin expression in cancer. SPCA2 is a secretory pathway Ca 2+ -ATPase that is down-regulated in metastatic breast cancer. We show that SPCA2 is tightly co-expressed with epithelial signature genes and required for E-cadherin biogenesis and cell surface expression.Unexpectedly, this function is uncoupled from Ca 2+ pumping and mediated by binding to E-cadherin. Loss of SPCA2 is sufficient to disrupt cell-cell adhesion in tumorspheres and elicit mesenchymal gene expression through Hippo-YAP signaling. These findings point to a causal link between low SPCA2 levels and the epithelial-mesenchymal transition required for breast cancer metastasis.

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The N-cadherin cytoplasmic domain confers anchorage-independent growth and the loss of contact inhibition

Cited by 14 publications

References 60 publications

A central role for cadherin signaling in cancer

A central role for cadherin signaling in cancer

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells

A Ca²⁺-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

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The N-cadherin cytoplasmic domain confers anchorage-independent growth and the loss of contact inhibition

Cited by 14 publications

References 60 publications

A central role for cadherin signaling in cancer

A central role for cadherin signaling in cancer

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial–Mesenchymal Transition in Breast Cancer Cells

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

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A Ca²⁺-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells