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Originally published as MBC in Press, 10.1091/mbc.E08-11-1149 on February 11, 2009

Vol. 20, Issue 7, 2030-2040, April 1, 2009

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Tetraspanin Proteins Regulate Membrane Type-1 Matrix Metalloproteinase-dependent Pericellular Proteolysis

Marc A. Lafleur, Daosong Xu, and Martin E. Hemler

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115

Submitted November 26, 2008; Revised January 27, 2009; Accepted January 29, 2009
Monitoring Editor: Jean E. Schwarzbauer

Membrane type-1 matrix metalloproteinase (MT1-MMP) supports tumor cell invasion through extracellular matrix barriers containing fibrin, collagen, fibronectin, and other proteins. Here, we show that simultaneous knockdown of two or three members of the tetraspanin family (CD9, CD81, and TSPAN12) markedly decreases MT1-MMP proteolytic functions in cancer cells. Affected functions include fibronectin proteolysis, invasion and growth in three-dimensional fibrin and collagen gels, and MMP-2 activation. Tetraspanin proteins (CD9, CD81, and TSPAN2) selectively coimmunoprecipitate and colocalize with MT1-MMP. Although tetraspanins do not affect the initial biosynthesis of MT1-MMP, they do protect the newly synthesized protein from lysosomal degradation and support its delivery to the cell surface. Interfering with MT1-MMP-tetraspanin collaboration may be a useful therapeutic approach to limit cancer cell invasion and metastasis.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E08-11-1149) on February 11, 2009.

Address correspondence to: Martin E. Hemler (martin_hemler{at}dfci.harvard.edu)

Abbreviations used: GFP, green fluorescent protein; MMP, matrix metalloproteinase; MT1-MMP, membrane type-1 matrix metalloproteinase; TEM, tetraspanin-enriched microdomain.




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