Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 105, Issue 1, Pages 25-33Publisher
WILEY-LISS
DOI: 10.1002/jcb.21821
Keywords
cell morphology; cell spreading; matrix metalloproteinase; epithelial-mesenchymal transition; Rac1b; TGF beta; micropatterned substrata; mammary epithelial cells; reactive oxygen species
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Funding
- Office of Biological and Environmental Research of the Department of Energy [DE-AC03-76SF00098]
- National Cancer Institute [CA64786, CA57621, CA122086, CA128660]
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Cell morphology dictates response to a wide variety of stimuli, controlling cell metabolism, differentiation, proliferation, and death. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells acquire migratory characteristics, and in the process convert from a cuboidal epithelial structure into an elongated mesenchymal shape. We had shown previously that matrix metalloproteinase-3 (MMP3) can stimulate EMT of cultured mouse mammary epithelial cells through a process that involves increased expression of Rac1b, a protein that stimulates alterations in cytoskeletal structure. We show here that cells treated with MMP-3 or induced to express Rac1b spread to cover a larger surface, and that this induction of cell spreading is a requirement of MMP-3/Rac1b-induced EMT. We find that limiting cell spreading, either by increasing cell density or by culturing cells on precisely defined micropatterned substrata, blocks expression of characteristic markers of EMT in cells treated with MMP-3. These effects are not caused by general disruptions in cell signaling pathways, as TGF-beta-induced EMT is not affected by similar limitations on cell spreading. Our data reveal a previously unanticipated cell shape-dependent mechanism that controls this key phenotypic alteration and provide insight into the distinct mechanisms activated by different EMT-inducing agents.
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