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| Content Provider | Journal of Biological Chemistry (JBC) |
|---|---|
| Author | Radjabi, A. Reza Sawada, Kenjiro Jagadeeswaran, Sujatha Eichbichler, Alfred Kenny, Hilary A. Montag, Anthony Bruno, Katharina Lengyel, Ernst |
| Abstract | The procoagulatory serine protease, thrombin, is known to induce invasion and metastasis in various cancers, but the mechanisms by which it promotes tumorigenesis are poorly understood. Because the 92-kDa gelatinase (MMP-9) is a known mediator of tumor cell invasion, we sought to determine whether and how thrombin regulates MMP-9. The thrombin receptor, PAR-1, and MMP-9 are expressed in osteosarcomas, as determined by immunohistochemistry. Stimulation of U2-OS osteosarcoma cells with thrombin and a thrombin receptor-activating peptide induced pro-MMP-9 secretion as well as cell surface-associated pro-MMP-9 expression and proteolytic activity. This was paralleled by an increase in MMP-9 mRNA and MMP-9 promoter activity. Thrombin-induced invasion of U2-OS cells through Matrigel was mediated by the phosphatidylinositol 3-kinase signaling pathway and could be inhibited with an MMP-9 antibody. The stimulation of MMP-9 by thrombin was paralleled by an increase in β1-integrin mRNA and β1-integrin expression on the cell surface, which was also mediated by phosphatidylinositol 3-kinase and was required for invasion. Thrombin activation induced and co-localized both β1-integrin and pro-MMP-9 on the cell membrane, as evidenced by co-immunoprecipitation, confocal microscopy, and a protein binding assay. The thrombin-mediated association of these two proteins, as well as thrombin-mediated invasion of U2-OS cells, could be blocked with a cyclic peptide and with an antibody preventing binding of the MMP-9 hemopexin domain to β1-integrin. These results suggest that thrombin induces expression and association of β1-integrin with MMP-9 and that the cell surface localization of the protease by the integrin promotes tumor cell invasion. |
| Related Links | http://www.jbc.org/content/283/5/2822.abstract |
| Ending Page | 2834 |
| Starting Page | 2822 |
| Page Count | 13 |
| File Format | HTM / HTML PDF |
| ISSN | 00219258 |
| Journal | Journal of Biological Chemistry (JBC) |
| Issue Number | 5 |
| Volume Number | 283 |
| DOI | 10.1074/jbc.M704855200 |
| e-ISSN | 1083351X |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology |
| Publisher Date | 2008-02-01 |
| Access Restriction | Open |
| Subject Keyword | Mechanisms of Signal Transduction |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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