Activation of Matrix Metalloproteinase-2 (MMP-2) by Membrane Type 1 Matrix Metalloproteinase through an Artificial Receptor for ProMMP-2 Generates Active MMP-2
| Autor: | Yuki Nishida, Hisashi Miyamori, Takahisa Takino, Yoshio Endo, Hiroshi Sato, Erik W. Thompson |
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| Rok vydání: | 2008 |
| Předmět: |
Signal peptide
Cancer Research medicine.medical_treatment Chick Embryo Biology Matrix metalloproteinase Polymerase Chain Reaction Cell Line Enzyme activator Cell Line Tumor Matrix Metalloproteinase 14 medicine Animals Humans Neoplasm Metastasis Phosphorylation Receptor DNA Primers Protease Base Sequence Molecular biology Transmembrane protein Enzyme Activation Transmembrane domain Oncology Cell culture Matrix Metalloproteinase 2 |
| Zdroj: | Cancer Research. 68:9096-9104 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 金沢大学がん研究所がん病態制御 The suggested model for pro-matrix metalloproteinase-2 (proMMP-2) activation by membrane type 1 MMP (MT1-MMP) implicates the complex between MT1-MMP and tissue inhibitor of MMP-2 (TIMP-2) as a receptor for proMMP-2. To dissect this model and assess the pathologic significance of MMP-2 activation, an artificial receptor for proMMP-2 was created by replacing the signal sequence of TIMP-2 with cytoplasmic/transmembrane domain of type II transmembrane mosaic serine protease (MSP-T2). Unlike TIMP-2, MSP-T2 served as a receptor for proMMP-2 without inhibiting MT1-MMP, and generated TIMP-2-free active MMP-2 even at a low level of MT1-MMP. Thus, MSP-T2 did not affect direct cleavage of the substrate testican-1 by MT1-MMP, whereas TIMP-2 inhibited it even at the level that stimulates proMMP-2 processing. Expression of MSP-T2 in HT1080 cells enhanced MMP-2 activation by endogenous MT1-MMP and caused intensive hydrolysis of collagen gel. Expression of MSP-T2 in U87 glioma cells, which express a trace level of endogenous MT1-MMP, induced MMP-2 activation and enhanced cell-associated protease activity, activation of extracellular signal-regulated kinase, and metastatic ability into chick embryonic liver and lung. MT1-MMP can exert both maximum MMP-2 activation and direct cleavage of substrates with MSP-T2, which cannot be achieved with TIMP-2. These results suggest that MMP-2 activation by MT1-MMP potentially amplifies protease activity, and combination with direct cleavage of substrate causes effective tissue degradation and enhances tumor invasion and metastasis, which highlights the complex role of TIMP-2. MSP-T2 is a unique tool to analyze physiologic and pathologic roles of MMP-2 and MT1-MMP in comparison with TIMP-2. ©2008 American Association for Cancer Research.全文公開200911 |
| Databáze: | OpenAIRE |
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