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Vol. 20, Issue 14, 3224-3238, July 15, 2009

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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, and Patricia J. Keely^*,

*Department of Pharmacology and Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI 53706; Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06520; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104; and ^||Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, CA 94143

Submitted December 11, 2008; Revised April 22, 2009; Accepted May 13, 2009
Monitoring Editor: Yu-Li Wang

InCytes from MBC

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-β1 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-β1 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.

Address correspondence to: Patricia J. Keely (pjkeely{at}wisc.edu)

Abbreviations used: FILIP, filamin A-interacting protein; FLNa, filamin A; MLC, myosin light chain; MPLSM, multiphoton laser-scanning microscopy; SHG, second-harmonic generation.

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