期刊
EXPERIMENTAL CELL RESEARCH
卷 263, 期 2, 页码 209-223出版社
ELSEVIER INC
DOI: 10.1006/excr.2000.5118
关键词
gelatinase A; integrin alpha v beta 3; metalloproteinases; MMP-2; MT1-MMP; TIMP-2
资金
- NCI NIH HHS [CA69306, CA83017, CA77470] Funding Source: Medline
- NHLBI NIH HHS [HL58925] Funding Source: Medline
We evaluated cellular mechanisms involved in the activation pathway of matrix prometalloproteinase-2 (pro-MMP-2), an enzyme implicated in the malignant progression of many tumor types. Membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves the N-terminal prodomain of pro-NIMP-2 thus generating the activation intermediate that then matures into the fully active enzyme of MMP-2. Our results provide evidence on how a collaboration between MT1-MMP and integrin alphav beta3 promotes more efficient activation and specific, transient docking of the activation intermediate and, further, the mature, active enzyme of MMP-2 at discrete regions of cells. We show that coexpression of MT1-MMP and integrin alphav beta3 in MCF7 breast carcinoma cells specifically enhances in trans autocatalytic maturation of MMP-2. The association of MMP-2's C-terminal hemopexin-like domain with those molecules of integrin alphav beta3 which are proximal to MT1-MMP facilitates MMP-2 maturation. Vitronectin, a specific ligand of integrin alphav beta3, competitively blocked the integrin-dependent maturation of MMP-2. Immunofluorescence and immunoprecipitation studies supported clustering of MT1-MMP and integrin alphav beta3 at discrete regions of the cell surface. Evidently, the identified mechanisms appear to be instrumental to clustering active MMP-2 directly at the invadopodia and invasive front of alphav beta3-expressing cells or in their close vicinity, thereby accelerating tumor cell locomotion. (C) 2001 Academic Press.
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