Filamin A-beta1 integrin complex tunes epithelial cell response to matrix tension

Mol Biol Cell. 2009 Jul;20(14):3224-38. doi: 10.1091/mbc.e08-12-1186. Epub 2009 May 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Cell Line, Tumor
  • Collagen / metabolism
  • Contractile Proteins / metabolism*
  • Epithelial Cells / metabolism*
  • Extracellular Matrix / metabolism*
  • Filamins
  • Gels / metabolism
  • Humans
  • Integrin beta1 / metabolism*
  • Mice
  • Microfilament Proteins / metabolism*
  • Morphogenesis
  • Myosin Light Chains / metabolism
  • Phosphorylation
  • Protein Binding

Substances

  • Contractile Proteins
  • Filamins
  • Gels
  • Integrin beta1
  • Microfilament Proteins
  • Myosin Light Chains
  • Collagen