Filamin A–β1 integrin complex tunes epithelial cell response to matrix tension

Scott Gehler, Massimiliano Baldassarre, Yatish Lad, Jennifer L. Leight, Michele A. Wozniak, Kristin M. Riching, Kevin W. Eliceiri, Valerie M. Weaver, David A. Calderwood, Patricia J. Keely

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3224-3238
Number of pages15
JournalMolecular Biology of the Cell
Volume20
Issue number14
Early online date20 May 2009
DOIs
Publication statusPublished - 15 Jul 2009

Keywords

  • animals
  • antigens, CD29
  • biomechanics
  • cell line, tumor
  • collagen
  • contractile proteins
  • epithelial cells
  • extracellular matrix
  • gels
  • humans
  • mice
  • microfilament proteins
  • morphogenesis
  • myosin light chains
  • phosphorylation
  • protein binding

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    Gehler, S., Baldassarre, M., Lad, Y., Leight, J. L., Wozniak, M. A., Riching, K. M., Eliceiri, K. W., Weaver, V. M., Calderwood, D. A., & Keely, P. J. (2009). Filamin A–β1 integrin complex tunes epithelial cell response to matrix tension. Molecular Biology of the Cell, 20(14), 3224-3238. https://doi.org/10.1091/mbc.E08-12-1186