title: Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells.
abstract: Mouse mammary epithelial cells undergo transdifferentiation via epithelial-mesenchymal transition (EMT) upon treatment with matrix metalloproteinase-3 (MMP3). In rigid microenvironments, MMP3 upregulates expression of Rac1b, which translocates to the cell membrane to promote induction of reactive oxygen species and EMT. Here we examine the role of the extracellular matrix (ECM) in this process. Our data show that the basement membrane protein laminin suppresses the EMT response in MMP3-treated cells, whereas fibronectin promotes EMT. These ECM proteins regulate EMT via interactions with their specific integrin receptors. α6-integrin sequesters Rac1b from the membrane and is required for inhibition of EMT by laminin. In contrast, α5-integrin maintains Rac1b at the membrane and is required for the promotion of EMT by fibronectin. Understanding the regulatory role of the ECM will provide insight into mechanisms underlying normal and pathological development of the mammary gland.
authors: Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
authors: Qike K
authors: QK
authors: Chen
authors: KangAe
authors: K
authors: Lee
authors: Derek C
authors: DC
authors: Radisky
authors: Celeste M
authors: CM
authors: Nelson
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000494:pharmacology*; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology*; D008321:Mammary Glands, Animal / Q000166:cytology*; D019278:Matrix Metalloproteinase 3 / Q000494:pharmacology*; D051379:Mice; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D005353:Fibronectins; D039482:Integrin alpha5; D039503:Integrin alpha6; D007797:Laminin; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: Alpha-smooth muscle actin; BM; Basement membrane; Cell shape; ECM; EMT; EMyT; Epithelial–mesenchymal transition; Epithelial–myofibroblast transition; Extracellular matrix; Integrin; Laminin-rich ECM; MMP3; Matrix metalloproteinase-3; Mechanical stress; ROS; Reactive oxygen species; TGFβ; Transforming growth factor-beta; lrECM; αSMA
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