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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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The American Society for Cell Biology
2015
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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. |
format | Online Article Text |
id | pubmed-4603929 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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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