Tetraspanin proteins regulate membrane type-1 matrix metalloproteinase-dependent pericellular proteolysis.
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.
Lafleur
Marc A
MA
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Xu
Daosong
D
Hemler
Martin E
ME
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D004795:Enzyme Stability; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D013347:Subcellular Fractions / Q000201:enzymology
D005353:Fibronectins; D008565:Membrane Proteins; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14