The Inactive 44-kDa Processed Form of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Enhances Proteolytic Activity via Regulation of Endocytosis of Active MT1-MMP
| Autor: | Allen Saliganan, Pamela Osenkowski, Lucia Schuger, Seaho Kim, Amro Aboukameel, Marta Toth, Huiren Zhao, Rafael Fridman, Jin Ah Cho, Kristina Cole, R. Daniel Bonfil |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Proteases
Cell macromolecular substances Biology Matrix metalloproteinase Endocytosis Models Biological Biochemistry Catalysis Gene Expression Regulation Enzymologic Cell membrane Cytosol stomatognathic system Cell Line Tumor Matrix Metalloproteinase 14 medicine Animals Humans Neoplasm Metastasis Molecular Biology Enzyme Catalysis and Regulation Cell Membrane Haplorhini Cell Biology Recombinant Proteins Cell biology Gene Expression Regulation Neoplastic medicine.anatomical_structure Cell culture embryonic structures HT1080 Collagen |
| Zdroj: | Journal of Biological Chemistry. 283:17391-17405 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m708943200 |
| Popis: | Membrane type 1 (MT1) matrix metalloproteinase (MMP-14) is a membrane-tethered MMP considered to be a major mediator of pericellular proteolysis. MT1-MMP is regulated by a complex array of mechanisms, including processing and endocytosis that determine the pool of active proteases on the plasma membrane. Autocatalytic processing of active MT1-MMP generates an inactive membrane-tethered 44-kDa product (44-MT1) lacking the catalytic domain. This form preserves all other enzyme domains and is retained at the cell surface. Paradoxically, accumulation of the 44-kDa form has been associated with increased enzymatic activity. Here we report that expression of a recombinant 44-MT1 (Gly285–Val582) in HT1080 fibrosarcoma cells results in enhanced pro-MMP-2 activation, proliferation within a three-dimensional collagen I matrix, and tumor growth and lung metastasis in mice. Stimulation of pro-MMP-2 activation and growth in collagen I was also observed in other cell systems. Expression of 44-MT1 in HT1080 cells is associated with a delay in the rate of active MT1-MMP endocytosis resulting in higher levels of active enzyme at the cell surface. Consistently, deletion of the cytosolic domain obliterates the stimulatory effects of 44-MT1 on MT1-MMP activity. In contrast, deletion of the hinge turns the 44-MT1 form into a negative regulator of enzyme function in vitro and in vivo, suggesting a key role for the hinge region in the functional relationship between active and processed MT1-MMP. Together, these results suggest a novel role for the 44-kDa form of MT1-MMP generated during autocatalytic processing in maintaining the pool of active enzyme at the cell surface. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|