Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2(Timp-2) gene alters proMMP-2 activation.
To understand the biologic function of TIMP-2, a member of the tissue inhibitors of metalloproteinases family, an inactivating mutation was introduced in the mouse Timp-2 gene by homologous recombination. Outbred homozygous mutants developed and procreated indistinguishably from wild type littermates, suggesting that fertility, development, and growth are not critically dependent on TIMP-2. Lack of functional TIMP-2, however, dramatically altered the activation of proMMP-2 both in vivo and in vitro. Fully functional TIMP-2 is essential for efficient activation of proMMP-2 in vivo. No evidence of successful functional compensation was observed. The results illustrate the duality of TIMP-2 function, i.e. at low concentrations, TIMP-2 exerts a "catalytic" or enhancing effect on cell-mediated proMMP-2 activation, whereas at higher concentrations, TIMP-2 inhibits the activation and/or activity of MMP-2.
Caterina
J J
JJ
NIDCR Matrix Metalloproteinase Unit and NIDCR Gene Targeting Research and Core Facility, National Institutes of Health, Bethesda, Maryland, 20892-4380, USA. jc239h@nih.gov
Yamada
S
S
Caterina
N C
NC
Longenecker
G
G
Holmbäck
K
K
Shi
J
J
Yermovsky
A E
AE
Engler
J A
JA
Birkedal-Hansen
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D018093:Gelatinases / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D011995:Recombination, Genetic; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism
D004792:Enzyme Precursors; D019716:Tissue Inhibitor of Metalloproteinase-2; D018093:Gelatinases; D008666:Metalloendopeptidases; C069860:progelatinase