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Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling

Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and...

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Autores principales: Archibald, Andrew, Al-Masri, Maia, Liew-Spilger, Alyson, McCaffrey, Luke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603929/
https://www.ncbi.nlm.nih.gov/pubmed/26269582
http://dx.doi.org/10.1091/mbc.E15-05-0265
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author Archibald, Andrew
Al-Masri, Maia
Liew-Spilger, Alyson
McCaffrey, Luke
author_facet Archibald, Andrew
Al-Masri, Maia
Liew-Spilger, Alyson
McCaffrey, Luke
author_sort Archibald, Andrew
collection PubMed
description Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant.
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spelling pubmed-46039292015-12-30 Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling Archibald, Andrew Al-Masri, Maia Liew-Spilger, Alyson McCaffrey, Luke Mol Biol Cell Articles Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant. The American Society for Cell Biology 2015-10-15 /pmc/articles/PMC4603929/ /pubmed/26269582 http://dx.doi.org/10.1091/mbc.E15-05-0265 Text en © 2015 Archibald et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Archibald, Andrew
Al-Masri, Maia
Liew-Spilger, Alyson
McCaffrey, Luke
Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title_full Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title_fullStr Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title_full_unstemmed Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title_short Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling
title_sort atypical protein kinase c induces cell transformation by disrupting hippo/yap signaling
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603929/
https://www.ncbi.nlm.nih.gov/pubmed/26269582
http://dx.doi.org/10.1091/mbc.E15-05-0265
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