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Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling...

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Autores principales: Lee, KangAe, Chen, Qike K., Lui, Cecillia, Cichon, Magdalena A., Radisky, Derek C., Nelson, Celeste M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469523/
https://www.ncbi.nlm.nih.gov/pubmed/22918955
http://dx.doi.org/10.1091/mbc.E12-02-0166
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author Lee, KangAe
Chen, Qike K.
Lui, Cecillia
Cichon, Magdalena A.
Radisky, Derek C.
Nelson, Celeste M.
author_facet Lee, KangAe
Chen, Qike K.
Lui, Cecillia
Cichon, Magdalena A.
Radisky, Derek C.
Nelson, Celeste M.
author_sort Lee, KangAe
collection PubMed
description Epithelial–mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT.
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spelling pubmed-34695232012-12-30 Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition Lee, KangAe Chen, Qike K. Lui, Cecillia Cichon, Magdalena A. Radisky, Derek C. Nelson, Celeste M. Mol Biol Cell Articles Epithelial–mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT. The American Society for Cell Biology 2012-10-15 /pmc/articles/PMC3469523/ /pubmed/22918955 http://dx.doi.org/10.1091/mbc.E12-02-0166 Text en © 2012 Lee 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 of Cell BD; are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Lee, KangAe
Chen, Qike K.
Lui, Cecillia
Cichon, Magdalena A.
Radisky, Derek C.
Nelson, Celeste M.
Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title_full Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title_fullStr Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title_full_unstemmed Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title_short Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition
title_sort matrix compliance regulates rac1b localization, nadph oxidase assembly, and epithelial–mesenchymal transition
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469523/
https://www.ncbi.nlm.nih.gov/pubmed/22918955
http://dx.doi.org/10.1091/mbc.E12-02-0166
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