TY - JOUR
T1 - Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition
AU - Lee, Kang Ae
AU - Chen, Qike K.
AU - Lui, Cecillia
AU - Cichon, Magdalena A.
AU - Radisky, Derek C.
AU - Nelson, Celeste M.
PY - 2012/10/15
Y1 - 2012/10/15
N2 - 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.
AB - 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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U2 - 10.1091/mbc.E12-02-0166
DO - 10.1091/mbc.E12-02-0166
M3 - Article
C2 - 22918955
AN - SCOPUS:84867454107
SN - 1059-1524
VL - 23
SP - 4097
EP - 4108
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 20
ER -