title: ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix.
abstract: 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.
authors: Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
authors: Michele A
authors: MA
authors: Wozniak
authors: Radhika
authors: R
authors: Desai
authors: Patricia A
authors: PA
authors: Solski
authors: Channing J
authors: CJ
authors: Der
authors: Patricia J
authors: PJ
authors: Keely
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D005782:Gels / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042361:Mammary Glands, Human / Q000166:cytology / Q000254:growth & development*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
chemical_list: D005782:Gels; D047908:Intracellular Signaling Peptides and Proteins; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins