The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis

被引:630
作者
Oh, J
Takahashi, R
Kondo, S
Mizoguchi, A
Adachi, E
Sasahara, RM
Nishimura, S
Imamura, Y
Kitayama, H
Alexander, DB
Ide, C
Horan, TP
Arakawa, T
Yoshida, H
Nishikawa, SI
Itoh, Y
Seiki, M
Itohara, S
Takahashi, C
Noda, M
机构
[1] Kyoto Univ, Grad Sch Med, Dept Mol Oncol, Sakyo Ku, Kyoto 6068501, Japan
[2] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Sakyo Ku, Kyoto 6068501, Japan
[3] Kyoto Univ, Grad Sch Med, Dept Anat & Neurobiol, Sakyo Ku, Kyoto 6068501, Japan
[4] Kyoto Univ, Grad Sch Med, Dept Mol Genet, Sakyo Ku, Kyoto 6068501, Japan
[5] Kitasato Univ, Grad Sch Med Sci, Dept Mol Morphol, Kanagawa 2288555, Japan
[6] RIKEN, Brain Res Inst, Wako, Saitama 3510198, Japan
[7] Amgen Inc, Amgen Ctr, Thousand Oaks, CA 91320 USA
[8] Univ Tokyo, Inst Med Sci, Dept Canc Res, Tokyo 1080071, Japan
关键词
D O I
10.1016/S0092-8674(01)00597-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK,expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.
引用
收藏
页码:789 / 800
页数:12
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