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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...

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Autores principales: Osborne, Lukas D., Li, George Z., How, Tam, O'Brien, E. Tim, Blobe, Gerard C., Superfine, Richard, Mythreye, Karthikeyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
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.
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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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