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

Kang Ae Lee, Qike K. Chen, Cecillia Lui, Magdalena A. Cichon, Derek C. Radisky, Celeste M. Nelson

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4097-4108
Number of pages12
JournalMolecular biology of the cell
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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