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TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion
Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell–cell adhesions...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230614/ https://www.ncbi.nlm.nih.gov/pubmed/25143398 http://dx.doi.org/10.1091/mbc.E14-05-1015 |
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author | Osborne, Lukas D. Li, George Z. How, Tam O'Brien, E. Tim Blobe, Gerard C. Superfine, Richard Mythreye, Karthikeyan |
author_facet | Osborne, Lukas D. Li, George Z. How, Tam O'Brien, E. Tim Blobe, Gerard C. Superfine, Richard Mythreye, Karthikeyan |
author_sort | Osborne, Lukas D. |
collection | PubMed |
description | Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell–cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)–induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5–enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β–induced EMT. |
format | Online Article Text |
id | pubmed-4230614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-42306142015-01-20 TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion Osborne, Lukas D. Li, George Z. How, Tam O'Brien, E. Tim Blobe, Gerard C. Superfine, Richard Mythreye, Karthikeyan Mol Biol Cell Articles Recent studies implicate a role for cell mechanics in cancer progression. The epithelial-to-mesenchymal transition (EMT) regulates the detachment of cancer cells from the epithelium and facilitates their invasion into stromal tissue. Although classic EMT hallmarks include loss of cell–cell adhesions, morphology changes, and increased invasion capacity, little is known about the associated mechanical changes. Previously, force application on integrins has been shown to initiate cytoskeletal rearrangements that result in increased cell stiffness and a stiffening response. Here we demonstrate that transforming growth factor β (TGF-β)–induced EMT results in decreased stiffness and loss of the normal stiffening response to force applied on integrins. We find that suppression of the RhoA guanine nucleotide exchange factors (GEFs) LARG and GEF-H1 through TGF-β/ALK5–enhanced proteasomal degradation mediates these changes in cell mechanics and affects EMT-associated invasion. Taken together, our results reveal a functional connection between attenuated stiffness and stiffening response and the increased invasion capacity acquired after TGF-β–induced EMT. The American Society for Cell Biology 2014-11-05 /pmc/articles/PMC4230614/ /pubmed/25143398 http://dx.doi.org/10.1091/mbc.E14-05-1015 Text en © 2014 Osborne 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 Osborne, Lukas D. Li, George Z. How, Tam O'Brien, E. Tim Blobe, Gerard C. Superfine, Richard Mythreye, Karthikeyan TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title | TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title_full | TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title_fullStr | TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title_full_unstemmed | TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title_short | TGF-β regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion |
title_sort | tgf-β regulates larg and gef-h1 during emt to affect stiffening response to force and cell invasion |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230614/ https://www.ncbi.nlm.nih.gov/pubmed/25143398 http://dx.doi.org/10.1091/mbc.E14-05-1015 |
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