The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.
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.
Oh
J
J
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, 606-8501, Kyoto, Japan.
Takahashi
R
R
Kondo
S
S
Mizoguchi
A
A
Adachi
E
E
Sasahara
R M
RM
Nishimura
S
S
Imamura
Y
Y
Kitayama
H
H
Alexander
D B
DB
Ide
C
C
Horan
T P
TP
Arakawa
T
T
Yoshida
H
H
Nishikawa
S
S
Itoh
Y
Y
Seiki
M
M
Itohara
S
S
Takahashi
C
C
Noda
M
M
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D058851:GPI-Linked Proteins; D018390:Gene Targeting; D006801:Humans; D007150:Immunohistochemistry; D053511:Matrix Metalloproteinase 14; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D014162:Transfection; D014407:Tumor Cells, Cultured
D058851:GPI-Linked Proteins; D061965:Matrix Metalloproteinase Inhibitors; D008562:Membrane Glycoproteins; C507096:Mmp14 protein, mouse; C115460:RECK protein, human; C492025:Reck protein, mouse; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14