Breast epithelial cells differentiate into tubules when cultured in floating three-dimensional (3D) collagen gels, but not when the cells are cultured in the same collagen matrix that is attached to the culture dish. These observations suggest that the biophysical properties of collagenous matrices regulate epithelial differentiation, but the mechanism by which this occurs is unknown. Tubulogenesis required the contraction of floating collagen gels through Rho and ROCK-mediated contractility. ROCK-mediated contractility diminished Rho activity in a floating 3D collagen gel, and corresponded to a loss of FAK phosphorylated at Y397 localized to 3D matrix adhesions. Increasing the density of floating 3D collagen gels also disrupted tubulogenesis, promoted FAK phosphorylation, and sustained high Rho activity. These data demonstrate the novel finding that breast epithelial cells sense the rigidity or density of their environment via ROCK-mediated contractility and a subsequent down-regulation of Rho and FAK function, which is necessary for breast epithelial tubulogenesis to occur.
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10 November 2003
Article|
November 10 2003
ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix
Michele A. Wozniak,
Michele A. Wozniak
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
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Radhika Desai,
Radhika Desai
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
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Patricia A. Solski,
Patricia A. Solski
2Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27510
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Channing J. Der,
Channing J. Der
2Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27510
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Patricia J. Keely
Patricia J. Keely
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
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Michele A. Wozniak
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
Radhika Desai
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
Patricia A. Solski
2Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27510
Channing J. Der
2Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27510
Patricia J. Keely
1Department of Pharmacology, University of Wisconsin, Madison, WI 53706
Address correspondence to Patricia J. Keely, Department of Pharmacology, University of Wisconsin, 3630 MSC, 1300 University Ave., Madison, WI 53706. Tel.: (608) 265-2398. Fax: (608) 262-1257. email: [email protected]
Abbreviations used in this paper: 2D, two-dimensional; 3D, three-dimensional; FAK, focal adhesion kinase; FAK pY397, FAK phosphorylated on tyrosine 397; HGF, hepatocyte growth factor; MLC, myosin light chain; MLCK, MLC kinase; ROCK, Rho kinase.
Received:
May 02 2003
Accepted:
September 17 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 163 (3): 583–595.
Article history
Received:
May 02 2003
Accepted:
September 17 2003
Citation
Michele A. Wozniak, Radhika Desai, Patricia A. Solski, Channing J. Der, Patricia J. Keely; ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix . J Cell Biol 10 November 2003; 163 (3): 583–595. doi: https://doi.org/10.1083/jcb.200305010
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