title: Filamin A-beta1 integrin complex tunes epithelial cell response to matrix tension.
abstract: The physical properties of the extracellular matrix (ECM) regulate the behavior of several cell types; yet, mechanisms by which cells recognize and respond to changes in these properties are not clear. For example, breast epithelial cells undergo ductal morphogenesis only when cultured in a compliant collagen matrix, but not when the tension of the matrix is increased by loading collagen gels or by increasing collagen density. We report that the actin-binding protein filamin A (FLNa) is necessary for cells to contract collagen gels, and pull on collagen fibrils, which leads to collagen remodeling and morphogenesis in compliant, low-density gels. In stiffer, high-density gels, cells are not able to contract and remodel the matrix, and morphogenesis does not occur. However, increased FLNa-beta1 integrin interactions rescue gel contraction and remodeling in high-density gels, resulting in branching morphogenesis. These results suggest morphogenesis can be "tuned" by the balance between cell-generated contractility and opposing matrix stiffness. Our findings support a role for FLNa-beta1 integrin as a mechanosensitive complex that bidirectionally senses the tension of the matrix and, in turn, regulates cellular contractility and response to this matrix tension.
authors.affiliation: Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Gehler
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Baldassarre
authors.forename: Yatish
authors.initials: Y
authors.lastname: Lad
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Leight
authors.forename: Michele A
authors.initials: MA
authors.lastname: Wozniak
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Riching
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D003285:Contractile Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D064448:Filamins; D005782:Gels / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009024:Morphogenesis; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D005782:Gels; D019012:Integrin beta1; D008840:Microfilament Proteins; D018994:Myosin Light Chains; D003094:Collagen