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Vol. 19, Issue 12, 5529-5540, December 2008

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Matrix Metalloproteinase 2-Integrin vβ3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study

Paul A. Rupp^*,, Richard P. Visconti^,, András Czirók^*,, David A. Cheresh^||, and Charles D. Little^*

*Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160; Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425; Department of Biological Physics, Eötvös University, H-1117 Budapest, Hungary; and ^||Department of Pathology, University of California, San Diego, La Jolla, CA 92093

Submitted May 23, 2007; Revised August 26, 2008; Accepted October 2, 2008
Monitoring Editor: Marianne Bronner-Fraser

InCytes from MBC

Cellular invasive behavior through three-dimensional collagen gels was analyzed using computational time-lapse imaging. A subpopulation of endocardial cells, derived from explanted quail cardiac cushions, undergoes an epithelial-to-mesenchymal transition and invades the substance of the collagen gels when placed in culture. In contrast, other endocardial cells remain epithelial and move over the gel surface. Here, we show that integrin vβ3 and matrix metalloproteinase (MMP)2 are present and active in cushion mesenchymal tissue. More importantly, functional assays show that mesenchymal invasive behavior is dependent on MMP2 activity and integrin vβ3 binding. Inhibitors of MMP enzymatic activity and molecules that prevent integrin vβ3 binding to MMP2, via its hemopexin domain, result in significantly reduced cellular protrusive activity and invasive behavior. Computational analyses show diminished intensity and persistence time of motility in treated invasive mesenchymal cells, but no reduction in motility of the epithelial-like cells moving over the gel surface. Thus, quantitative time-lapse data show that mesenchymal cell invasive behavior, but not epithelial cell locomotion over the gel surface, is partially regulated by the MMP2–integrin interactions.

These authors contributed equally to this work.

Address correspondence to: Charles D. Little (clittle{at}kumc.edu).

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InCytes from MBC, December 2008

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